KR20200070425A - Droplet delivery device for delivery of fluids to the pulmonary system and methods of use - Google Patents

Abstract

A droplet delivery device and related methods for delivering precise and repeatable doses to a subject for use in the lung are disclosed. The droplet delivery device includes a housing, reservoir, and ejector mechanism, and at least one differential pressure sensor. The droplet delivery device is automatically breathed by the user when the differential pressure sensor detects a predetermined pressure change in the housing. The droplet delivery device is then operated to generate a stream of droplets having an average ejection droplet diameter within the respirable size range, eg, less than about 5 μm, to target the user's disposal relationship.

Description

A droplet delivery device and a method of use for delivery of fluids to a waste relationship {DROPLET DELIVERY DEVICE FOR DELIVERY OF FLUIDS TO THE PULMONARY SYSTEM AND METHODS OF USE}

Cross reference to related applications

This application is filed under Article 119 of the United States Patent Act: United States Provisional Patent Application No. 62/331,328, filed May 3, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/332,352, filed May 5, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/334,076, filed May 10, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/354,437 filed on June 24, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/399,091 filed on September 23, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/416,026 filed on November 1, 2016, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; Filed on November 16, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE", US Provisional Patent Application No. 62/422,932, filed November 16, 2016; United States Provisional Patent Application No. 62/428,696 filed on December 1, 2016, filed on December 1, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; United States Provisional Patent Application No. 62/448,796, filed Jan. 20, 2017, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE"; And the priority of U.S. Provisional Patent Application No. 62/471,929, filed March 15, 2017, entitled "DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE". The contents of each application are incorporated herein by reference in their entirety.

Field of invention

The present disclosure relates to droplet delivery devices, and more particularly, to droplet delivery devices for delivery of fluids to a waste relationship.

The use of aerosol-generating devices for the treatment of various respiratory diseases is of great interest. Inhalation provides delivery of aerosolized drugs that treat asthma, COPD and site specific conditions with reduced systemic adverse effects. The main challenge is to provide a device that delivers accurate, consistent, verifiable dosages in droplet sizes suitable for successful delivery of medicines to targeted lung channels.

Dosage verification, delivery and inhalation of the correct dose at defined times is important. It is also a significant problem to have patients use their inhalers properly. There is a need to ensure that patients are using the inhalers properly and that they are administering the appropriate dosages at specified times. Problems arise when patients misuse or improperly administer their medications. Unexpected results occur when the patient stops taking medications because he does not feel any benefit, or when he does not see the expected benefits or abuses the medications to increase the risk of overdose. Doctors also face the question of how to interpret and diagnose the prescribed treatment when the treatment results are not obtained.

Currently, most inhaler systems, such as metered dose inhalers (MDI) and pressurized metered dose inhalers (p-MDI) or pneumatic and ultrasonically driven devices, have high momentum. And droplets with high velocity and a wide range of droplet sizes, including large droplets with kinetic energy. These high momentum droplets and aerosols do not reach the distal lung or lower lung passages, but are deposited in the mouth and throat. As a result, larger total drug doses are required to achieve the desired deposition in target areas. These large doses increase the probability of unwanted side effects.

Aerosol plumes generated from current aerosol delivery systems result in localized cooling of the drug on the ejector surfaces and subsequent condensation, resulting in high ejection rates of the smoke and rapid expansion of the drug delivery propellant, It can also lead to deposition and crystallization. Blockage of ejector openings by deposited drug residue is also a problem.

This surface condensation phenomenon is also a challenge to existing vibrating mesh or aperture plate sprayers available on the market. In these systems, in order to prevent the accumulation of drugs on the mesh opening surfaces, manufacturers require repeated cleaning and cleaning, as well as single-use disinfection to prevent possible microbial contamination. Other challenges include the delivery of viscous drugs and suspensions that can block openings or holes and can lead to inefficient or incorrect drug delivery to patients or render the device inoperable. In addition, the use of detergents or other cleaning or sterile fluids may lead to uncertainty regarding the device's ability or the device's ability to damage the ejector mechanism or other parts of the nebulizer and deliver the correct dose to the patient.

Thus, the inhaler device delivers particles in a suitable size range, avoids clogging of surface fluid deposits and openings with verifiable dosing, and provides feedback regarding the correct and consistent use of the inhaler to patients and experts such as physicians, pharmacists or therapists. There is a need to provide.

In one aspect, the present disclosure is directed to a piezoelectrically operated droplet delivery device that delivers fluid as a discharged stream of droplets to a subject's disposal relationship. The droplet delivery device includes: a housing; A storage tank disposed in the housing or in fluid communication with the housing to receive a volume of fluid; A discharger mechanism in fluid communication with a reservoir, the discharger mechanism includes a piezoelectric actuator and an opening plate, the opening plate having a plurality of openings formed through its thickness and the piezoelectric actuator vibrating the opening plate by one frequency The ejector mechanism operable to generate an ejected stream of droplets; At least one differential pressure sensor located within the housing; The at least one differential pressure sensor configured to generate an ejected stream of droplets by actuating an ejector mechanism upon sensing a predetermined pressure change in the housing; The ejector mechanism configured to generate an ejected stream of droplets, wherein at least about 70% of the droplets have an average ejection droplet diameter of less than about 5 microns, so that at least about 70% of the mass of the ejected stream of droplets is used It may include the ejector mechanism, which is delivered in a respirable range to the target's disposal relationship.

In certain aspects, further comprising a surface tension plate between the opening plate and the reservoir, the surface tension plate is configured to increase the contact between the volume of fluid and the opening plate. In other aspects, the ejector mechanism and surface tension plate are configured in parallel orientation. In still other aspects, the surface tension plate is positioned within 2 mm of the opening plate to create sufficient hydrostatic force to provide capillary flow between the surface tension plate and the opening plate.

In still other aspects, the opening plate of the droplet delivery device comprises a dome shape. In other aspects, the opening plate comprises poly ether ether ketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene ( ultra-high molecular weight polyethylene) (UHMWPE), Ni, NiCo, Pd, Pt, NiPd, metal alloys, and combinations thereof. In other aspects, one or more of the plurality of apertures provides ejected droplets having different average ejection droplet diameters by having different cross-sectional shapes or diameters.

In some aspects, the droplet delivery device is located on the airflow inlet side of the housing and facilitates laminar airflow across the outlet side of the opening plate and the ejected stream of droplets is in use. It further includes a laminar flow element configured to provide sufficient airflow to ensure flow through. In other aspects, the droplet delivery device may further include a mouthpiece coupled with the housing opposite the laminar flow element.

In other aspects the ejector mechanism of the droplet delivery device is oriented relative to the housing such that the ejected stream of droplets proceeds through the housing and traverses the housing at approximately 90 degree orbit before exiting the housing.

In still other aspects, the reservoir of the droplet delivery device is detachably coupled to the housing. In other aspects, the reservoir of the droplet delivery device is coupled to the ejector mechanism to form a combination reservoir/discharger mechanism module, and the combination reservoir/discharger mechanism module is detachably coupled to the housing.

In other aspects, the droplet delivery device may further include a wireless communication module. In some aspects, the wireless communication module is a Bluetooth transmitter.

In still other aspects, the droplet delivery device may further include one or more sensors selected from infrared transmitters, photodetectors, additional pressure sensors, and combinations thereof.

In a further aspect, the present disclosure is directed to a respiratory actuated droplet delivery device that delivers fluid as a discharged stream of droplets to a subject's disposal relationship. The device includes: a housing; A combination reservoir/discharger mechanism module that is in fluid communication with the housing to receive a volume of fluid and generate a discharged stream of droplets; A discharger mechanism comprising a piezoelectric actuator and an opening plate having a dome shape, wherein the opening plate has a plurality of openings formed through its thickness and the piezoelectric actuator vibrates the opening plate at a frequency to discharge the stream of droplets The ejector mechanism operable to generate a; At least one differential pressure sensor located within the housing; At least one differential pressure sensor configured to activate the ejector mechanism to generate an ejected stream of droplets upon sensing a predetermined pressure change in the housing when the subject exhales inspiration on the airflow outlet side of the housing; An ejector mechanism configured to generate an ejected stream of droplets, wherein at least about 70% of the droplets have an average ejection droplet diameter of less than about 5 microns, such that at least about 70% of the mass of the ejected stream of droplets is in use It may also include the ejector mechanism, which is delivered in a respirable range to the subject's disposal relationship.

In other aspects, the dome-shaped opening plate of the respiratory actuated droplet delivery device comprises poly ether ether ketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), Ni, NiCo, Pd, Pt, NiPd, metal alloys, and combinations thereof.

In other aspects, the respiratory actuated droplet delivery device is located on the airflow inlet side of the housing and facilitates the layer airflow to cross the outlet side of the opening plate and the ejected stream of droplets is passed through the droplet delivery device in use. And a laminar flow element configured to provide sufficient airflow to ensure flowing. In still other aspects, the respiratory actuated droplet delivery device further comprises a mouthpiece coupled with the housing opposite the laminar flow element.

In a further aspect, the present disclosure relates to a method of filtering large droplets from aerosolized smoke using inertial forces. The method may include generating a discharged stream of droplets using a droplet delivery device, wherein the ejector mechanism proceeds into the housing at a trajectory of approximately 90 degrees before the ejected stream of droplets is discharged from the housing. Oriented relative to the housing to pass through the housing; And droplets having a diameter greater than about 5 μm are deposited on the side walls of the housing due to inertial forces, without being transported through the droplet delivery device to the enclosed air stream to the object's disposal relationship.

In another aspect, the present disclosure relates to a method for generating and delivering fluid within a respirable range to a subject's disposal relationship as a discharged stream of droplets. The method comprises: (a) generating an ejected stream of droplets through a piezoelectrically operated droplet delivery device, wherein at least about 70% of the ejected stream of droplets has an average ejection droplet diameter of less than about 5 μm; Generating; And (b) delivering the ejected stream of droplets to the subject's discard relationship such that at least about 70% of the mass of the ejected stream of droplets is delivered in a respirable range to the subject's discard relationship during use.

In other aspects, the ejected stream of droplets of the disclosed method allows droplets having a diameter greater than about 5 μm without being conveyed through the piezoelectrically operated droplet delivery device to the enclosed air stream to the subject's disposal relationship. The inertia forces undergo an orbital change of approximately 90 degrees within the piezoelectrically operated droplet delivery device to be filtered from the ejected stream of droplets. In still other aspects, filtering of droplets having a diameter greater than about 5 μm increases the mass of the ejected stream of droplets delivered to the subject's disposal relationship during use. In other aspects, the ejected stream of droplets may further include droplets having an average ejection droplet diameter between about 5 μm and about 10 μm. In further aspects, the ejected stream of droplets may include a therapeutic agent to treat a lung disease, disorder, or condition.

In further aspects, a piezoelectrically operated droplet delivery device includes: a housing; A reservoir disposed in the housing or in fluid communication with the housing to receive a volume of fluid; A discharger mechanism in fluid communication with a reservoir, the discharger mechanism includes a piezoelectric actuator and an opening plate, the opening plate having a plurality of openings formed through its thickness and the piezoelectric actuator vibrating the opening plate by one frequency The ejector mechanism operable to generate an ejected stream of droplets; And at least one differential pressure sensor located in the housing, configured to generate an ejected stream of droplets by actuating the ejector mechanism upon sensing a predetermined pressure change in the housing. It may include.

In other further aspects, the opening plate of the piezoelectrically operated droplet delivery device comprises a dome shape. In other aspects, the piezoelectrically operated droplet delivery device is located on the airflow inlet side of the housing and facilitates layer airflow across the outlet side of the opening plate and the ejected stream of droplets is passed through the droplet delivery device in use. And a laminar flow element configured to provide sufficient airflow to ensure flowing.

The present invention will be more clearly understood from the following description given as an example, among the drawings:
1A is a diagram showing automatic breathing operation and inertial filtering using a droplet delivery device according to one embodiment of the present disclosure.
1B-1E show an example of a suction detection system that senses airflow by detecting pressure differences across a flow restriction. 1B and 1C , exemplary locations and limitations of pressure sensors are shown. 1B is an example where the restrictions are inside the mouthpiece tube. 1C is an example where the restriction is placed on a laminar flow element and pressure is sensed as the difference between the pressure inside the mouthpiece tube and outside the tube. 1D is a screen capture of the delta P sensor response to inhaled breath with a duration of ˜1 second. 1E is a Delta P sensor design and assembly on its device board 1 . The sensor has a pneumatic connection through a hole in a printed circuit board (PCB) and on the main PCB as shown by schemes ( 2 ) or on a daughter board to scheme ( 3 ). It may be mounted on any one of the.
2A is a cross-sectional view of a droplet delivery device according to one embodiment of the present disclosure. 2B is an enlarged view of the ejector mechanism according to one embodiment of FIG. 2A.
2C is an exploded view of a droplet delivery device.
2D is a top view of a mouthpiece tube according to one embodiment of the present disclosure.
2E is a front view of a mouthpiece tube with an air opening grid or opening, according to one embodiment of the present disclosure.
3A is another embodiment of a droplet delivery device, FIG. 3B is an enlarged view of the ejector mechanism of the device of FIG. 3A , and FIG. 3C is an enlarged view of the surface tension plate of the device of FIG. 3A according to one embodiment of the present disclosure. to be.
4A-4C show one embodiment of a combination reservoir/discharger mechanism module, in accordance with one embodiment of the present disclosure, FIG. 4A shows an exploded view of the module, and FIG. 4B is an exemplary method for limiting evaporation A side view of a superhydrophobic filter and a micron sized opening is shown, and FIG. 4C provides a cross-sectional view and a top view of a module and mechanism for mechanical mounting of the ejector mechanism to the reservoir.
5A-5G provide an exemplary ejector closing mechanism, according to one embodiment of the present disclosure. 5A illustrates the ejector closing mechanism in the open position and FIG. 5B illustrates the ejector closing mechanism in the closed position. 5C- 5E illustrate detailed views of an exemplary ejector closing mechanism according to one embodiment of the present disclosure, including the top cover of FIG. 5C and the motors in the operating stages of FIGS. 5D and 5E . 5F and 5G provide an exploded view of an exemplary ejector closing mechanism according to one embodiment of the present disclosure.
6A is a plot of differential pressure as a function of flow rates through laminar flow elements mounted on a droplet delivery device of the present disclosure, expressed as a function of the number of holes.
6B is a diagram of the differential pressure as a function of flow rates through the laminar element as a function of screen hole size and the number of holes set to a constant 17 holes.
6C is a diagram of an air inlet laminar flow screen with 29 holes, each hole having a diameter of 1.9 mm.
7A and 7B depict exemplary ejector mechanism designs, in accordance with embodiments of the present disclosure.
8A and 8B depict perspective and side views of an exemplary dome-shaped opening plate design, in accordance with embodiments of the present disclosure.
9 depicts an opening plate opening design, in accordance with embodiments of the present disclosure.
10A and 10B are frequency sweep diagrams displaying media damping effects on resonant frequency for flat aperture plates ( FIG. 10A ) and dome shaped aperture plates ( FIG. 10B ), according to embodiments of the present disclosure . admit.
11 shows the amplitude and excitation voltage of the displacement of the dome-shaped opening plate from 50 kHz to 150 kHz; It is a graph of frequency change based on DHM compared to 5 Vpp. The enlarged ones are Eigen mode shapes associated with resonant frequencies of 59 kHz, 105 kHz, and 134 kHz.
Figure 12a and 12b illustrate the relationship between in accordance with the disclosed embodiment of the water, the opening plate and the dome height of the active area diameter. In FIG. 12A , d is the active area diameter and h is the opening plate dome height. 12B shows a diagram of the calculation of the opening plate height and the dome height relative to the active area.
13 is an exploded view of a reservoir containing a flexible drug ampoule, according to one embodiment of the present disclosure.
14A and 14B are top views of an exemplary surface tension plate, according to one embodiment of the present disclosure.
15A shows an exemplary top view of a surface tension plate according to one embodiment of the present disclosure.
15B illustrates the effect of the aperture plate (average of five, 2.2 second operations) from the aperture plate and surface tension plate composition on mass deposition.
16A illustrates a cross-section of a dual combination reservoir/discharger mechanism module, according to one embodiment of the present disclosure.
16B illustrates a droplet delivery device with a dual combination reservoir/discharger mechanism module, according to one embodiment of the present disclosure.
17A is a recorded negative image for droplet generation by a droplet delivery device, according to one embodiment of the present disclosure.
17B shows the droplet flow from the droplet delivery device of the present disclosure, an area ( 1 ) representing the area of laminar flow and an area ( 2 ) representing the area of turbulence due to the occurrence of splash entrained air, further from aerosol smoke. Illustrates a diagram of inertial filtering that filters out and excludes large droplets. The droplets undergo a 90 degree change in the direction of spraying ( 4-5 ) before being inhaled into the lung airway as the droplets exit the ejector mechanism and are swept by the airflow 3 through the laminar flow elements.
Figure 17c and Figure 17d depicts the inertial filter having a mechanism for selecting the droplet size distribution by varying the droplet exit angle.
Figure 18a and 18b are (Fig. 18a) magenta (deep red) LED (650 nm ) and / or (Fig. 18b) near (near) IR LED (850 nm ) are examples of spray verified using a laser and a photodiode detector.
19 illustrates a system comprising a droplet delivery device in combination with a mechanical respirator, in accordance with certain embodiments of the present disclosure.
20 illustrates a system incorporating a droplet delivery device in combination with a CPAP machine, according to certain embodiments of the present disclosure, such as to support cardiac events during sleep.
21A provides a summary of the mass fraction collected during Anderson Cascade Impactor testing of the droplet delivery device of the present disclosure.
21B is a summary of MMAD and GSD droplet data obtained during Anderson Cascade impactor testing of the droplet delivery device of the present disclosure (3 cartridges, 10 operations per cartridge; albuterol, 0.5%, 28.3 lpm; total 30 operations ).
21C-1 and 21C-2 are cumulative diagrams of the aerodynamic size distribution of the data displayed in FIG. 21A.
21D is a summary of the neck, coarse, respirable, and fine particle fractions. Anderson Cascade Impactor tests the droplet delivery device of the present disclosure (3 cartridges 10 runs per cartridge; albuterol, 0.5%, 28.3 lpm; total 30 runs).
22A and 22B are comparisons of aerosol smoke from the droplet delivery device of this disclosure ( FIG. 22A ) and aerosol smoke from Respimat Soft Mist Inhale ( FIG. 22B ).
FIG. 23A is a comparison of MMAD and GSD data for the droplet delivery device, lespimat, and ProAir inhaler devices of the present disclosure (Anderson Cascade Impactor Testing, 28.3 lpm, average +/- SD, 3 devices) , Works 10 times per device).
23B is a summary of the coarse, respirable, and microfractions for the droplet delivery device, lespimat, and proair inhaler devices of the present disclosure (Anderson Cascade Impactor Testing, 28.3 lpm, average +/- SD, 3 devices) , Works 10 times per device).
24A and 24B show SEC chromatographs of a control ( FIG. 24A ) and aerosolized Enbrel solutions (FIG. 24B) produced using the droplet delivery device of the present disclosure.
25A and 25B show SEC chromatographs of a control ( FIG. 25A ) and aerosolized insulin solutions ( FIG. 25B ) produced using a droplet delivery device of the present disclosure.

Effective delivery of medicines through the alveoli to the deep lung areas of the lungs has always caused problems due to their limited lung capacity and narrowing of the breathing pathways, especially in children and the elderly, as well as those in diseased states. The effect of the narrowed pulmonary passages limits the synchronization of the administered dose with deep inspiration and intake/exhalation cycles. For optimal deposition in the alveolar airways, particles with aerodynamic diameters in the range of 1 to 5 μm are optimal, particles less than about 4 μm were guided to reach the alveolar area of the lungs, while larger particles are placed on the tongue. It is deposited or hits the throat and is coated in the bronchial passages. Smaller particles, for example less than about 1 μm, penetrating deeper into the lungs tend to exhale.

In certain aspects, the present disclosure provides a droplet delivery device for delivering fluid as a discharged stream of droplets to a subject's disposal relationship, and associated methods of delivering a safe, suitable, and repeatable dose to a subject's disposal relationship. It is about. The present disclosure is capable of delivering a volume of fluid defined in the form of an ejected stream of droplets such that a suitable and repeatable high percentage of droplets are delivered into a desired location within the subject's airways, eg, alveolar airways, during use. It also includes delivery devices and systems.

The present disclosure provides a droplet delivery device for delivery of fluid as a discharged stream of droplets to a subject's disposal relationship, the device comprising a housing, a reservoir housing a volume of fluid, and a piezoelectric actuator and an opening plate It includes an ejector mechanism, the ejector mechanism being configured to eject a stream of droplets having an average ejection droplet diameter of less than 5 microns. In certain embodiments, the ejector mechanism is activated upon sensing a predetermined pressure change inside the housing by at least one differential pressure sensor located inside the housing of the droplet delivery device. In certain embodiments, this predetermined pressure change may be sensed by the user of the device during the intake cycle, as will be described in more detail herein.

According to certain aspects of the present disclosure, effective deposition into the lungs generally requires droplets less than 5 μm in diameter. Without wishing to be bound by theory, in order to deliver fluid to the lungs, the droplet delivery device must impart a momentum high enough to allow ejection out of the device but low enough to prevent deposits on the tongue or behind the throat. Droplets below 5 μm in diameter are almost completely transported not by their own momentum, but by the motion of the entrained air and airflow carrying them.

In certain aspects, the present disclosure includes and provides an ejector mechanism configured to eject a stream of droplets within a respirable range of less than 5 μm. The ejector mechanism includes an opening plate coupled directly or indirectly to the piezoelectric actuator. In certain implementations, the opening plate may be coupled to an actuator plate that is coupled to a piezoelectric actuator. The opening plate generally includes a plurality of openings formed through its thickness and the piezoelectric actuator, when the patient inhales, has an opening plate having a fluid contacting one surface of the opening plate, the aerosol proceeding of the droplets The stream vibrates directly or indirectly (eg, through an actuator plate) at a frequency and voltage that develops into the lungs through openings in the opening plate. In other embodiments where the opening plate is coupled to the actuator plate, the actuator plate is The piezoelectric oscillator is vibrated at a frequency and voltage that generates a running aerosol stream or smoke of aerosol droplets.

In certain aspects, the present disclosure relates to a droplet delivery device that delivers fluid as a discharged stream of droplets to a subject's disposal relationship. In certain aspects, therapeutic agents may be delivered at high dose concentrations and efficacy compared to alternative dosing routes and standard inhalation techniques.

In certain embodiments, droplet delivery devices of the present disclosure may be used to treat a variety of diseases, disorders and conditions by delivering therapeutic agents to the subject's disposal. In this regard, droplet delivery devices may be used to deliver therapeutic agents both locally to the disposal relationship and systemically to the body.

More specifically, the droplet delivery device may be used to treat lung diseases or disorders such as asthma, chronic obstructive pulmonary diseases (COPD) cystic fibrosis (CF), tuberculosis, chronic bronchitis, or pneumonia, or It can also be used to deliver therapeutic agents to the subject's disposal relationship as a discharged stream of droplets for prevention. In certain embodiments, a droplet delivery device may be used to deliver therapeutic agents such as COPD medications, asthma medications, or antibiotics. As a non-limiting example, these therapeutic agents include albuterol sulfate, ipratropium bromide, tobramycin, and combinations thereof.

In other embodiments, a droplet delivery device may be used for systemic delivery through the disposal of therapeutic agents, including small molecules, therapeutic peptides, proteins, antibodies, and other biotechnology molecules. As a non-limiting example, the droplet delivery device is for the treatment or prevention of indications including, for example, diabetes mellitus, rheumatoid arthritis, plaque psoriasis, Crohn's disease, hormone replacement, neutropenia, nausea, influenza, etc. It can also be used to deliver therapeutic agents systemically.

By way of non-limiting example, therapeutic peptides, proteins, antibodies, and other biotechnology molecules include: growth factors, insulin, vaccines (Prevnor-pneumonia, Gardasil-HPV), antibodies ( Avastin, Humira, Remicade, Herceptin, Fc fusion proteins (Enbrel, Orencia), hormones (Elonva-sustained release FSH, growth hormone) , Enzymes (Pulmozyme-rHu-DNAase- ), other proteins (coagulation factors, interleukins, albumin), gene therapy and RNAi, cell therapy (Provenge-prostate cancer Vaccines), antibody drug conjugates-Adcetris (Brentuximab vedotin for HL), cytokines, anti-infectives, polynucleotides, oligonucleotides ( Eg, gene vectors), or any combination thereof; Or solid particles or suspensions such as Flonase (fluticasone propionate) or Advair (fluticasone propionate and salmeterol xinafoate) Includes

In other embodiments, the droplet delivery device of the present disclosure delivers a nicotine solution comprising a water-nicotine azeotrope for delivery of highly controlled doses for conditions that require smoking cessation or medical or veterinary treatment. It can also be used to In addition, the fluid may contain THC, CBD, or other chemicals contained in marijuana for the treatment of seizures and other conditions.

In certain embodiments, the drug delivery device of the present disclosure can be used when the dosing is enabled only by physician or pharmacy communication to the device, and the dosing is as confirmed by the GPS location on the patient's smart phone. It may also be used to deliver scheduled and controlled substances, such as drugs, for highly controlled dispensing of pain medications, if they may only be possible at certain locations, such as residence. This mechanism of highly controlled dosing of controlled medications can prevent abuse or overdose of drugs or other addictive medications.

Certain advantages of the pulmonary pathway for the delivery of drugs and other medicines are compared to the non-invasive, needleless delivery system, GI tract suitable for delivery of a wide range of substances from small molecules to very large proteins. And reduced levels of metabolic enzymes, and that the absorbed molecules do not experience the first pass effect. (A. Tronde, et al., J Pharm Sci , 92 (2003) 1216-1233; AL Adjei, et al., Inhalation Delivery of Therapeutic Peptides and Proteins, M. Dekker, New York, 1997). In addition, medications administered orally or intravenously are diluted as they pass through the body, while medications given directly into the lungs may provide concentrations about 100 times higher than the same intravenous dose at the target site (lungs). . This is particularly important for the treatment of drug-resistant bacteria, drug-resistant tuberculosis, and the increasing problem in drug-resistant bacterial infections in the ICU, for example.

Another advantage of providing medication directly into the lungs is that high, toxic levels of medications in the bloodstream associated with side effects can be minimized. For example, intravenous administration of tobramycin leads to very high serum levels that poison the kidneys and therefore its use is limited, whereas administration by inhalation significantly reduces lung function without serious side effects on kidney functions. Improve. (Ramsey et al., Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med 1999;340:23-30; MacLusky et al., Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa Pediatr Pulmonol 1989;7:42-48; Geller et al., Pharmacokinetics and bioavailablility of aerosolized tobramycin in cystic fibrosis.Chest 2002;122:219-226.)

As discussed above, effective delivery of droplets deep into the lung airways requires droplets less than 5 microns in diameter, specifically droplets with mass mean aerodynamic diameters (MMAD) less than 5 microns. Shall be The mass average aerodynamic diameter is defined as the diameter where the mass is 50% larger and 50% smaller. In certain aspects of the present disclosure, in order to deposit in the alveolar airways, droplet particles in this size range are high enough to allow ejection out of the device, but sufficient to overcome deposition onto the tongue (panel) or pharynx. You must have low momentum.

In other aspects of the present disclosure, methods are provided for generating an ejected stream of droplets for delivery to a user's disposal relationship using the droplet delivery devices of the present disclosure. In certain embodiments, the ejected stream of droplets is generated with a controllable and defined droplet size range. By way of example, the droplet size range is at least about 50%, at least about 60%, at least about 70%, at least about 85%, at least about 90%, between about 50% and about 90%, about 60% and about of the ejected droplets Between 90%, between about 70% and about 90%, etc., are in the respirable range below about 5 μm.

In other embodiments, the ejected stream of droplets may have one or more diameters such that droplets with multiple diameters have multiple regions in the airways (mouth, tongue, neck, upper airways, lower airways, Deep lung, etc.). By way of example, droplet diameters range from about 1 μm to about 200 μm, from about 2 μm to about 100 μm, from about 2 μm to about 60 μm, from about 2 μm to about 40 μm, from about 2 μm to about 20 μm, from about 1 μm. To about 5 μm, about 1 μm to about 4.7 μm, about 1 μm to about 4 μm, about 10 μm to about 40 μm, about 10 μm to about 20 μm, about 5 μm to about 10 μm, and combinations thereof It may be a range. In certain embodiments, at least a portion of the droplets have diameters within the respirable range, while other particles may have diameters of different sizes (eg, greater than 5 μm) to target nonrespirable locations. Exemplary ejected droplet streams in this regard breathe 50% to 70% of the droplets in the respirable range (less than about 5 μm) and breathing (such as about 5 μm to about 10 μm, about 5 μm to about 20 μm, etc.) It may have 30% to 50% outside the possible range.

In other embodiments, methods are provided for delivering a medicament of safe, suitable, and repeatable doses into a discard relationship using the droplet delivery devices of the present disclosure. The methods deliver the ejected stream of droplets to a desired location within the subject's discard relationship, including the deep lungs and alveolar airways.

In certain aspects of the present disclosure, a droplet delivery device is provided that delivers an ejected stream of droplets to a subject's disposal relationship. The droplet delivery device generally includes a housing, a reservoir disposed in the housing and in fluid communication with the housing, an ejector mechanism in fluid communication with the reservoir, and at least one differential pressure sensor located within the housing. The differential pressure sensor is configured to activate the ejector mechanism upon sensing a predetermined pressure change in the housing, and the ejector mechanism is configured to generate controllable smoke of the ejected stream of droplets. The ejected stream of droplets contains, without limitation, solutions, suspensions or emulsions with viscosities within a range capable of droplet formation using the ejector mechanism. The ejector mechanism may include a piezoelectric actuator coupled directly or indirectly to an opening plate having a plurality of openings formed through its thickness. The piezoelectric actuator is operable to generate a discharged stream of droplets by vibrating the opening plate directly or indirectly at one frequency.

In certain embodiments, the droplet delivery device may be replaceable or disposable periodically, such as daily, weekly, monthly, as needed, which may be suitable for prescription or over-the-counter medicines. It may also include a combination reservoir/discharger mechanism module. The reservoir may be filled and stored in the pharmacy for future administration to patients, or it may be filled in a pharmacy or elsewhere by using a suitable infusion means such as a manually driven or micro-pump driven hollow infusion syringe. have. The syringe may fill the reservoir by pumping the fluid into a rigid container or other collapsible or non-foldable reservoir. In certain aspects, this disposable/replaceable, combination reservoir/discharger mechanism module may minimize and prevent the accumulation of surface deposits or surface microbial contamination on the opening plate due to its short use time.

The present disclosure also provides a highly insensitive droplet delivery device. In certain implementations, the droplet delivery device travels by airplane when the user moves from sea level to sub-sea levels and at high altitudes, for example, pressure differences may be as high as 4 psi. It is configured not to be sensitive to pressure differences that may occur during the process. As will be discussed in more detail herein, in certain implementations of the present disclosure, the droplet delivery device provides free interchange of air across the filter into and out of the reservoir, but by blocking moisture or fluids passing through the filter, It may also include a superhydrophobic filter that reduces or prevents fluid leakage or deposition on the aperture plate surfaces.

Reference will now be made to the figures, and similar components are shown with like reference numbers.

Referring to FIG. 1A , in one aspect of the present disclosure, droplet delivery device 100 is illustrated in use by a patient. The droplet delivery device 100 may include one or more differential pressure sensors (not shown) that provide for automatic electronic breathing operation of the device. This pressure sensor(s) automatically detects the desired point during the user's intake cycle to generate the ejected stream of droplets to activate the ejector mechanism 104 . For example, a user initiates inhalation, pulling air through the back of the device at 1 , triggering a differential pressure sensor to activate the ejector mechanism 104 to generate a discharged stream of droplets at 2 , The stream of droplets may be moved along the device in 3 and into the user's airway by being entrained into the user's intake air stream. As will be described in more detail herein, any large droplets are removed from the entrained airflow through inertial filtering, falling at 4 to the bottom surface of the device. As a non-limiting example, the pressure sensor(s) may be programmed to trigger a 2 second discharge when the user generated airflow in the device is about 10 SLM or similar pressure. However, any suitable differential pressure within the target user's standard physiological range may be used. This trigger point during the inspiration cycle may provide an optimal point during the user's inhalation cycle to trigger and activate the delivery of the drug product and the generation of the ejected stream of droplets. Since electronic breathing operation does not require user device coordination, the droplet delivery devices and methods of the present disclosure further provide assurance for optimal delivery of inhaled medication.

As a non-limiting example, FIGS. 1B-1E illustrate inhalation detection systems according to embodiments of the present disclosure that sense airflow by detecting pressure differences across a flow restriction. As will be discussed in more detail below with reference to FIGS . 2A , 2C , and 3A , pressure sensors are limited to being inside the device, such as being within an aerosol delivery mouthpiece tube, and a droplet delivery device of the present disclosure. It may be located within. For example, FIG. 1B is an example where the restriction is inside the device tube, and FIG. 1C is an example where the restriction is at the air inlet laminar element. Pressure is sensed as the difference between the pressure inside and outside the device tube. 1D is a screen capture of an exemplary pressure sensor response to inhaled breath with a duration of ˜1 second. 1E illustrates exemplary differential pressure sensor designs and assemblies on device board 1 . The sensor may have a pneumatic connection through a hole in a printed circuit board (PCB) and either on the main PCB as shown below in scheme 2 or on the daughter board shown in scheme 3 It can also be mounted on.

Once activated, the droplet delivery device of the present disclosure may be operated to deliver an ejected stream of droplets for any suitable time sufficient to deliver the desired dosage. For example, the piezoelectric actuator may be activated to generate a discharged stream of droplets by oscillating the opening plate for a short burst of time, such as for a tenth of a second, or for several seconds, such as five seconds. . In certain embodiments, the droplet delivery device may be, for example, up to about 5 seconds, up to about 4 seconds, up to about 3 seconds, up to about 2 seconds, up to about 1 second, between about 1 second and about 2 seconds, about 0.5 seconds. And about 2 seconds, etc., may be activated to generate and deliver the ejected stream of droplets.

In certain embodiments, any suitable differential pressure sensor may be used, such as ± 5 SLM, 10 SLM, 20 SLM, etc., with appropriate sensitivity to measure pressure changes obtained during standard intake cycles. For example, Sensirion I&C. (Sensirion, Inc.), SDP31 or SDP32 (US 7,490,511 B2) pressure sensors are particularly well suited for these applications.

In certain embodiments of the present disclosure, the signal generated by the pressure sensors provides a trigger for activation and activation of the ejector mechanism of the droplet delivery device at or during the peak period of the patient's inspiratory cycle. And ensures optimal deposition of the ejected stream of droplets and delivery of medication into the user's lung airways.

By the way, may be provided with cameras, scanners, or other sensors, the limited image capturing device, for example, a charge coupled device (CCD), including without, to detect and measure the discharged aerosol smoke. All of these detectors, LEDs, Delta P transducers, and CCD devices are used to monitor, detect, measure, and control the discharge of fluids and report patient compliance, treatment times, dosages, and patient usage history. Signals that control the microprocessor or controller in the device are provided, for example, via Bluetooth.

In certain aspects of the present disclosure, the ejector mechanism, reservoir, and housing/mouthpiece function to generate smoke or aerosol of fluid having droplet diameters of less than 5 μm. As discussed above, in certain embodiments, the reservoir and ejector mechanism will deliver sufficient fluid for medication of a piezoelectric actuator powered by electronics in the device housing and only a few or hundreds of doses. It is integrated to form a combination reservoir/discharger mechanism module that may include a drug reservoir.

In certain embodiments, as illustrated herein, the combination module may have a pressure equalization port or filter that minimizes leakage during atmospheric pressure changes, such as on commercial aircraft. The combination module may also include components that may carry information read by the housing electronics including key parameters such as information related to actuator frequency and duration, drug identification, and patient dosing intervals. Some information may be added at the factory to the module, and some may be added at the pharmacy. In certain embodiments, information placed by the factory may be protected from modification by pharmacies. The module information may be carried as a printed barcode or as a physical barcode encoded into the module geometry (same as light transmitting holes on the flange read by sensors on the housing). Information may also be carried by programmable or non-programmable microchips on modules that communicate to electronics in the housing through piezoelectric power consumption. For example, each time the device is turned on, the cartridge may transmit a minimum voltage, e.g., 5 volts, over a piezoelectric power connection, causing the data chip to send a low-level pulse stream back to the electronics over the same power connection. have.

By way of example, module programming at a factory or pharmacy may include a drug code that is read by the device and which may be verified via Bluetooth to an appropriate user smartphone and then verified as appropriate for the user. When a user inserts a module such as inaccurate, general, and damaged into a device, the smartphone is prompted to lock the device's operation, thus providing a measure of user safety and security not possible with passive inhaler devices. It might be. In other embodiments, device electronics can limit use to a limited period of time (perhaps a day, or weeks or months) to avoid problems associated with drug aging or progressive accumulation of contamination on the aperture plate.

An airflow sensor located within the device aerosol delivery tube measures the inspiration and exhalation flows flowing in and out of the mouthpiece. The sensor is positioned so as not to interfere with drug delivery or to become a site for collection of residues or to promote bacterial growth or contamination. A differential (or gauge) pressure sensor downstream of the flow restrictor (e.g., laminar flow element) measures airflow based on the pressure difference between the inside of the mouthpiece and the outside air pressure. During inhalation (exhalation flow), the mouthpiece pressure will be lower than ambient pressure and during exhalation (exhalation flow), the mouthpiece pressure will be higher than ambient pressure. The magnitude of the pressure difference during the inspiration cycle is a measure of the magnitude of airflow and airway resistance at the air inlet end of the aerosol delivery tube.

In one embodiment, referring to FIG. 2A , the power/start button 132 ; Electronics circuit board 102 ; An ejector mechanism 104 having a piezoelectric actuator 106 and an opening plate 108 ; A reservoir 110 that may include an optional filter 110a on its surface; And an exemplary droplet delivery device 100 that includes a power source 112 (which may optionally be rechargeable) that is electronically coupled to the piezoelectric actuator 106 . In certain embodiments, reservoir 110 is coupled to ejector mechanism 104 to form a combination drug reservoir/dispenser mechanism module (see FIGS. 4A-4C ) that may be replaceable, disposable, or reusable . It can be ringed or integrated with the ejector mechanism. The droplet delivery device 100 further includes a power source 112 , which, when activated by the pressure sensor 122 upon sensing a predetermined change in pressure within the device, opens the opening plate 108 . Energy is supplied to the piezoelectric actuator 106 to vibrate so that the ejected stream of droplets is ejected through the opening plate 108 in a predefined direction. The droplet delivery device 100 may further include a surface tension plate 114 that advances and focuses the fluid, at least partially, into the opening plate 108 , as described further herein.

The components may be packaged within the housing 116 , which may be disposable or reusable. The housing 116 may be handheld, for example, communication with other devices via a Bluetooth communication module 118 or similar wireless communication module for communication with a subject's smartphone, tablet or smart device (not shown) It may be adapted to. In one embodiment, the laminar flow element 120 provides sufficient airflow to facilitate laminar flow across the outlet side of the opening plate 108 and to ensure that the discharged stream of droplets flows through the device during use. It may be located on the air inlet side of the housing 116 to provide. Aspects of this embodiment, as will be described in more detail herein, a droplet delivery device by varying configurations to allow placement of laminar flow elements having different sizes of openings and to selectively increase or decrease the internal pressure resistance. It is further allowed to customize the internal pressure resistance of the.

The droplet delivery device 100 , as described further herein, various sensors and detectors 122, 124, 126, and 128 that facilitate device activation, spray verification, patient compliance, diagnostic mechanisms, or As part of a larger network for data storage, big data analysis and interaction, it may further include interconnected devices used for target care and treatment. In addition, the housing 116 may include on its surface an LED assembly 130 indicating various status notifications, such as ON/READY, error, and the like.

2B , an enlarged view of the ejector mechanism 104 according to one embodiment of the present disclosure is illustrated. The ejector mechanism 104 may generally include a piezoelectric actuator 106 , an opening plate 108 , which includes a plurality of openings 108a formed through its thickness. The surface tension plate 114 may also be located on the fluid facing surface of the opening plate, as described in more detail herein. The piezoelectric actuator 106 is operable to generate a discharged stream of droplets through the plurality of openings 108a , for example, by vibrating the opening plate 108 at its resonant frequency. In certain embodiments, openings 108a and ejector mechanism 104 may be configured to generate an ejected stream of droplets having an MMAD of 5 μm or less.

The airflow outlet of the housing 116 of the droplet delivery device 100 of FIG. 2A passing through when the discharged stream of droplets is sucked into the airways of the subject is, without limitation, circular, oval, rectangular, hexagonal or other shapes While it may consist of a cross-sectional shape or may have such a cross-sectional shape, the shape of the length of the tube may, again, without limitation, be straight, curved or venturi-type.

In other embodiments (not shown), a mini fan or centrifugal blower may be located on the air inlet side of the laminar flow element 120 or inside the housing 116 within the airflow. Mini fans may also provide additional airflow and pressure to the output of the airflow. For patients with low lung output, this additional airflow may ensure that the ejected stream of droplets is pushed through the device into the patient's airway. In certain implementations, this additional airflow source also ensures to provide a mechanism that allows the ejected droplets to be cleaned cleanly on the front of the ejector and to spread droplet smoke to create an airflow that creates greater separation between the droplets. The airflow provided by the mini pan may also act as a carrier gas, ensuring proper dose dilution and delivery.

2C , another embodiment of a droplet delivery device of the present disclosure is shown in a developed view. Again, similar components are marked with similar reference numbers. The droplet delivery device 150 provides a cover for the aerosol delivery mouthpiece tube 154 and interfaces with the reservoir 110 top cover 152 , base handle 156 , start button 132 , and handle bottom Illustrated with a cover 158 .

A series of colored lights powered by the LED assembly is located in the front area of the ejector device. In this embodiment, the LED assembly 130 includes, for example, four LEDs 130A and an electronics board 130B , on which the LED assembly 130 is mounted and the main electronics An electrical connection is provided to the board 102 . The LED assembly 130 (as further described herein) provides feedback regarding when an effective or ineffective dose of the dosage is delivered, to signal when a breathing maneuver occurs (as described further herein). ), or other user feedback to maximize patient compliance, may provide the user with instant feedback on functions such as power, on and off.

The laminar flow element 120 is located opposite the patient use end of the mouthpiece tube 154 , the differential pressure sensor 122 , the pressure sensor electronics board 160 , and the pressure sensor O-ring 162 are located nearby do.

The remaining components detailed in FIG. 2C are located within the device handle 156, which is mounted for power 112 (eg, three, AAA batteries), upper and lower battery contacts 112A , 112B . Assembly 164 , and audio chips and speakers 166A, 166B .

Referring again to FIG. 2C , a Bluetooth communication module 118 or similar wireless communication module is provided to link the droplet delivery device 150 to a smartphone or other similar smart devices (not shown). Bluetooth connectivity facilitates the implementation of various software or apps that may provide and facilitate patient training for use of the device. The main obstacle to effective inhaler drug therapy has been either poor patient adherence to prescribed aerosol therapy or errors in the use of inhaler devices. By providing a real-time display on the smartphone screen leading to the patient's inspiration cycle, (flow rate versus time) and total volume, to the goal of the total inspiration volume previously established and recorded on the smartphone during the training session at the doctor's office. The patient may be challenged to reach. The Bluetooth connection provides prescribed medication therapy by providing a means to store and archive compliance information, or patient data and diagnostic data (either on a smartphone or in the cloud or data storage on another large network) that may be used for treatment. Easier patient compliance and accelerate compliance.

The aerosol delivery mouthpiece tube is removable, replaceable and may be sterile. This feature improves hygiene of drug delivery by providing means and methods to minimize the accumulation of aerosolized medicaments in the mouthpiece tube by providing easy replacement, disinfection and cleaning. In one embodiment, the mouthpiece tube may be formed using sterile and transparent polymer compositions such as, but not limited to, polycarbonate, polyethylene or polypropylene. Referring to FIG. 2D , an exemplary aerosol delivery mouthpiece tube 154 is shown, which is a circular port 168 through which an aerosol spray passes from an ejector mechanism (not shown), as well as a pressure sensor ( It includes the location of a slot 170 for receiving not shown). The choice of materials for the aerosol delivery mouthpiece tube should generally allow effective cleaning and should have electrostatic properties that do not impede or confine fluid droplets of interest. Unlike many spraying devices with larger droplets and higher dose rates, the mouthpiece of the present disclosure needs to be long or specially shaped to reduce the speed of large droplets that would otherwise affect the patient's mouth and neck. Does not.

In other embodiments, the internal pressure resistance of the droplet delivery device modifies the mouthpiece tube design to include various configurations of air opening grids or openings, increasing resistance to airflow through the device when the user inhales or It can also be tailored to individual users or groups of users by reducing it. For example, referring to FIG. 2E , an exemplary opening grid 172 in the mouthpiece tube opening is illustrated. However, different air inlet opening sizes and numbers may be used to achieve different internal device pressure values by achieving different resistance values. This feature provides a mechanism to quickly and easily adapt and customize the airway resistance of the droplet delivery device to the individual patient's health condition or condition.

3A-3C , another embodiment of a droplet delivery device of the present disclosure is illustrated. Again, similar components are illustrated with similar reference numbers. In the illustrated embodiment, the droplet ejector device 200 may include a vertically oriented ejector mechanism 104 . As illustrated, the droplet ejector device 200 includes an electronics circuit board 102 ; Ejector mechanism 104 including piezoelectric actuator 106 and opening plate 108 (FIG. 3B) ; Surface tension plate 114 (Fig. 3c), is coupled with optionally the discharge group mechanism 104 is replaceable, or one-time or or may form a reusable combined reservoir / discharge-based mechanism module reservoir 110 which, And a power source 112 coupled to the piezoelectric actuator 106 and a start button 132 . The power source 112 , when activated, provides energy to the piezoelectric actuator 106 to vibrate the opening plate 108 so that the stream of ejected droplets is ejected through the opening plate 108 in a predefined direction. will be. The components may be packaged within the housing 116 , which may be disposable or reusable. The housing 116 may be handheld or adapted for communication with other devices. For example, the Bluetooth module 118 may be adapted for communication with a patient's smart phone, tablet or smart device. Device 200 may include device activation, spray validation, one or more sensor or detector means ( 122 , 124 , 126 ) for patient compliance, diagnostic means, or part of a larger network for data storage and interaction and target care and treatment It may also include interconnected devices used for. The device may be single, two pieces or three pieces, including, for example, a disposable combination reservoir/discharger mechanism module, a disposable mouthpiece and a disposable or reusable electronics unit.

Any suitable material may be used to form the housing of the droplet delivery device. In certain embodiments, the material should be selected so that it does not interact with the components of the device or the fluid to be ejected (eg, drug or pharmaceutical ingredients). Gamma radiation compatible polymer materials suitable for use in, for example, pharmaceutical applications, such as polystyrene, polysulfones, polyurethanes, phenolic resins, polycarbonates, polyimides, aromatic polyesters (PET, PETG), etc. Polymer materials containing them may also be used.

In certain aspects of the present disclosure, to help reduce deposition of ejected droplets during use due to electrostatic charge build-up, one or more portions of the housing along which the electrostatic coating follows the airflow passage, such as, It can also be applied to the inner surfaces of the housing. Alternatively, one or more portions of the housing may be formed of a charge dissipating polymer. For example, conductive fillers are commercially available and more common polymers used in medical applications, such as PEEK, polycarbonate, polyolefins (polypropylene or polyethylene), or polystyrene or acrylic-butadiene- It can also be synthesized from styrenes, such as styrene (acrylic-butadiene-styrene) (ABS) copolymers.

As mentioned above, in certain configurations of the present disclosure, the reservoir and ejector mechanism may be integrated together into a combination reservoir/discharger mechanism module, which may be removable and/or one-time. In certain embodiments, the combination reservoir/discharger mechanism module may be oriented vertically such that the surface tension plate may facilitate fluid contact between the fluid in the reservoir and the fluid contact surface of the opening plate. In other configurations, the combination reservoir/discharger mechanism module may be oriented horizontally within the device and positioned such that fluid in the reservoir makes constant contact with the fluid contact surface of the opening plate.

For example, referring to FIGS. 4A-4C , the combination reservoir/discharger mechanism module 400 is a piezoelectric actuator 106 , an opening plate 108 , a surface tension plate 114 , and a discharger of the module 400 Illustrated including a guide 402 , filter 404 , and ejector mechanism housing 414 to facilitate and align insertion into the device (not shown). In certain embodiments, the filter 404 is two superhydrophobic filters, such as those provided by a polymer, metal or other composite material structure by Nitto Denko, Temish, high performance breathable porous membranes It includes a sandwich structure including a micro-sized opening 404B positioned between ( 404A ).

In certain embodiments, module 400 may further include a seal 404C that seals the filling hole used to administer the fluid into the ampoule. Other components include a polymer cap 406 that seals the top of the ampoule, a housing cup 408 including a surface tension plate 114 , an O-ring structure 410 supporting the opening plate 108 , and connector pins 412 ) Through a piezoelectric actuator 106 in electrical contact with the electronic device.

Also included in module 400 is to provide electrical contact and electrical feed to piezoelectric actuator 106 , as well as information about drug type, initial drug volume, concentration, such as single or multiple dosing regimens, dosing It is an optional bar code (not shown) that may provide dosing information such as frequency and dosing times. Additional information that may be included on the barcode may generally identify the type of opening plate, target droplet size distribution and target airway or site of action in the body. Alternatively, this information may be carried on an electronic chip embedded in a module that may be read through either a wireless connection or via a signal carried by a piezoelectric power connection or through one or more additional physical contacts. . The barcode or other information contained on the chip may provide cartridge identification or fatal drug content information that may prevent, for example, improper use or expiration of the device or accidental insertion of inappropriate medication.

In certain embodiments, the droplet delivery devices of the present disclosure may further include an ejector closing mechanism, which may provide a closing barrier to limit evaporation of reservoir fluid through the opening plate, and It may also provide a barrier to protection against contamination of the reservoir. As will be understood by those skilled in the art, with the reservoir, the ejector closing mechanism provides a protective enclosure of the reservoir/discharger mechanism module into the reservoir of evaporation loss, contamination, and/or foreign materials. The intrusion of can also be minimized during storage.

5A and 5B , an exemplary ejector closing mechanism 502 is shown in the ejector spray outlet port 504 ( FIG. 5A shows the ejector closing mechanism 502 in an open configuration and FIG. 5B Is shown in the ejector closing mechanism 502 closed configuration). The ejector closing mechanism can be opened and closed manually or operated electronically. In certain embodiments, the ejector closing mechanism may include one or more sensors that prevent operation of the ejector mechanism when the ejector closing mechanism is not open. In other embodiments, the ejector closing mechanism may be automatically powered when the droplet delivery device is energized, and/or the ejector closing mechanism may be pre-determined at a predetermined time interval after operation of administration, eg, 15 seconds. , 30 seconds, 1 minute, 5 minutes, 10 minutes, etc. can be closed automatically.

5C-5E , a more detailed view of an exemplary ejector closing mechanism is provided. The removal of the housing top cover 152 exposes the ejector closing actuation mechanism 506 including the closing guide 508 , the sliding sealing plate 510 , and the motor mechanism 512 , where the motor mechanism 512 is Upon activation, the motor mechanism may open and close the sliding sealing plate 510 . Any suitable small motor mechanism may be used, such as a piezoelectric driven and actuated screw and screw motor, such as an ultrasonic sweeper motor from SI Scientific Instruments (www.si-gmbh.de). . This mechanism may provide assurance of minimizing contamination of the opening plate or evaporation losses through the opening plate by maintaining a sufficiently sealed reservoir/discharger mechanism module. Figure 5f and 5g provides a more detailed view of the discharge mechanism closing group. The sliding sealing plate 510 and the closing guide 508 are shown in a developed view.

As described herein, the droplet delivery device of the present disclosure may generally include a laminar flow element located on the air inlet side of the housing. The laminar flow element, in part, provides sufficient airflow to facilitate the laminar airflow across the exit side of the opening plate and to ensure that the ejected stream of droplets flows through the droplet delivery device during use. The laminar flow element allows customization of the internal device pressure resistance by designing openings of different sizes and varying configurations to selectively increase or decrease the internal pressure resistance.

In certain embodiments, the laminar flow element is designed and constructed to provide optimum airway resistance that achieves the peak inspiration flows required for deep inhalation prompting delivery of ejected droplets deep into the lung airways. Laminar flow elements also function to promote laminar flow throughout the opening plate, which also serves to stabilize airflow reproducibility, stability and to ensure optimal precision with the delivered dose.

Without intending to be bound by theory, according to aspects of the present disclosure, the size, number, shape, and orientation of holes in the laminar flow element of the present disclosure may be configured to provide a desired pressure drop within the droplet delivery device. In certain embodiments, it may generally be desirable to provide a pressure drop that is not large enough to strongly influence the user's breathing or perception of breathing.

In this regard, FIG. 6A illustrates the relationship between flow rate and differential pressure through exemplary laminar flow elements of the present disclosure as a function of opening hole diameters (0.6 mm, 1.6 mm and 1.9 mm), while FIG. 6B illustrates the present disclosure. The differential pressure as a function of the flow rates through the laminar elements of water is illustrated as a function of the number of holes (29 holes, 23 holes, 17 holes). Laminar flow elements are mounted on droplet delivery devices similar to those provided in FIG. 2C .

Referring to Figure 6c , the flow rate versus differential pressure as a function of hole size is shown to have a linear relationship when the flow rate is plotted as a function of the square root of the differential pressure. The number of holes remains constant at 17 holes. These data provide a method for selecting a design for a laminar flow element to provide a model for the relationship between flow velocity and differential pressure, as well as providing the desired pressure resistance, as measured in a droplet delivery device similar to that provided in FIG. 2C . Gives

Inspiration flow rate (SLM) = C (SqRt) (pressure (Pa))

Element # Hole size (mm)
(17 holes) Pressure at 10 slm (Pa) Flow rate at 1000 Pa Equation constant (C) 0 1.9 6 149.56 4.73 One 2.4 2.1 169.48 5.36 2 2.7 1.7 203.16 6.43 3 3 1.3 274.46 8.68

Referring to FIG. 6D , a non-limiting exemplary laminar flow element with 29 holes each of 1.9 mm diameter is shown. However, the present disclosure is not so limited. For example, the laminar flow element has, for example, a diameter equal to the cross-sectional diameter of the air inlet tube from 0.1 mm in diameter (eg 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm) , May have hole diameters ranging from 4.5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, etc.), the number of holes being from 1, for example, the number of holes filling the laminar flow element area (eg, 30, 60, 90, 100, 150, etc.). The laminar flow element may be mounted on the air inlet side of the droplet delivery device as described herein. In certain implementations, the use of laminar flow elements with holes of different sizes, or the use of adjustable openings, may be used with young people. It may be required to accommodate differences among the old, small and large, and lungs of various lung conditions and associated inspiration flow rates. For example, if the opening is adjustable by the patient (perhaps by having a slotted ring that can be rotated), read the opening hole setting and position it to avoid accidental changes in the opening hole size and thus flow measurements. A method of locking the may be provided. Although pressure sensing is an accurate method for flow measurement, other embodiments are, for example, hot wires or thermistor types of flow rate measurement methods that lose heat at a rate proportional to the flow rate, movable blades (turbine flow meter technology) or springs It is also possible to use the mounting plate without limitation.

As described herein, the droplet delivery device of the present disclosure has an ejector having a piezoelectric actuator coupled directly or indirectly to the opening plate, the aperture plate having a plurality of openings formed through its thickness. It may also include mechanisms in general. The plurality of openings may have various shapes, sizes and orientations. FIG. 7a and FIG. 7b to, and the like are illustrative of the disclosure ejection mechanism group. 7A illustrates components of one configuration of the ejector mechanism of the present disclosure in which the piezoelectric actuator 106 is directly coupled to the opening plate, and FIG. 7B shows the piezoelectric actuator 106 to the opening plate 108 actuator plate Another configuration of the ejector mechanism of the present disclosure that may be indirectly coupled via ( 108b ) is illustrated. In the embodiment of FIG. 7B , the piezoelectric actuator 106 is coupled directly to the actuator plate 108b , which is then coupled directly to the opening plate 108 . Upon startup, the piezoelectric actuator 106 vibrates the actuator plate 108b , which in turn vibrates the opening plate 108 to generate a discharged stream of droplets.

The opening plate may have any suitable size, shape or material. For example, the opening plate may have a circular, annular, oval, square, rectangular, or generally polygonal shape. Moreover, according to aspects of the present disclosure, the opening plate may be generally flat or may have a concave or convex shape. In certain embodiments, the opening plate may have a generally dome or hemispherical shape. As a non-limiting example, with reference to FIGS. 8A and 8B , an exemplary opening plate 808 is shown where the openings 808a are generally positioned in a dome-shaped region.

In this regard, it has been unexpectedly discovered that in certain aspects of the present disclosure, improved ejector mechanism performance may be obtained with aperture plates that generally have a dome shape. Referring to FIGS. 10A and 10B , a comparison of the media damping effect of air to distilled water on the resonance frequency for a plane ( FIG. 10A ) versus dome shaped opening plates ( FIG. 10B ) is provided. These diagrams suggest that, compared to the ejector mechanism using flat opening plates, the ejector mechanisms using dome-shaped opening plates are more stable and less sensitive to viscosity, mass load and media damping effects. The ejector mechanisms using dome-shaped opening plates provide improved performance by maintaining a stable and optimal resonant frequency. In this regard, the droplet delivery device of the present disclosure, which generally includes an opening plate having a dome shape, is more accurate, consistent and verifiable administration with a droplet size distribution suitable for the successful delivery of a medicament to a subject's disposal relationship. The amount will be delivered to the subject.

Referring to FIG. 11 , Digital Holographic Microscopy (DHM) was applied to identify resonant frequencies of a dome-shaped aperture plate according to aspects of the present disclosure. Capture of instantaneous eigenmode shapes for vibrating, circular, dome-shaped opening plates, and amplitude of displacement at resonance are shown, as well as displacement for dome-shaped opening plates from 50 kHz to 150 kHz. Amplitude and excitation voltage; A corresponding graph of frequency change versus 5 Vpp is shown. Mode shapes associated with resonant frequencies 59 kHz, 105 kHz, and 134 kHz are shown as call-out images for a dome-shaped aperture plate. Unlike the predicted and experimentally verified eigenmodes associated with piezoelectrically operated circular and planar aperture plates, the eigenmodes associated with dome shaped aperture plates do not change the shape or eigenmodes with increasing excitation frequency, and the remaining aperture plate. It maintains the shape of the dome.

In certain implementations of the present disclosure, design parameters that define the dome-shaped geometry of an exemplary opening plate include the dome height, the active area (area containing multiple openings), and the shape and geometry of the dome. When FIG. 12a and FIG. 12b, the dome height (h) and the dome diameter (d) is defined by a circular arc which is formed having a diameter of a circle that contains the vertices of the outer edge parts of the active area by drawing (Fig. 12a). The resulting equation defining the parameters dome height and active area (base of the dome) is shown in FIG. 12B , which illustrates the relationship between the opening plate dome height and the active area diameter.

As indicated in the table below, performance comparisons of aperture plates using planar to dome shapes as compared to droplet generation efficiency as measured by ml of fluid ejected per minute show that the dome shape provides a significant improvement in performance.

Active area diameter (mm) Active area (mm ² ) Outlet hole diameter (㎛) Driving frequency (kHz) Excitation voltage (Vpp) Discharge volume (ml/min) Flat shape 6 28.27 4 113 40 0.5 Dome shape 2 3.14 3 109 30 0.7

These data show that a flat surface ejects 0.5 mL/min across the active surface area of the 28.3 mm ² footprint (area) and 0.7 mL/min from the only 3.1 mm ² active surface area footprint for pores with similar domed surfaces. Indicates that it is discharged. In other words, the domed surface discharges 12.6 times more mass per unit area of the active surface area footprint than the flat surface. The opening plate of the present disclosure is formed of any suitable material known in the art for these purposes. It may be. By way of non-limiting example, the opening plate may be a pure metal, metal alloy or high modulus polymeric material, such as, but not limited to, Ni, NiCo, Pd, Pt, NiPd, or other metal or alloy combinations, polyether ether ketone (PEEK) , Polyimide (Kapton), polyetherimide (Ultem), polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), as well as blending in polymers to improve physical and chemical properties A range of filler materials can be used for opening plate designs and fabrication. Filler materials may include, but are not limited to, glass and carbon nanotubes. These materials can also be used to increase yield strength and stiffness or modulus of elasticity. In one embodiment, the opening plate is an Optronics Preseason nose. Lt. (Optnics Precision Co. LTD.) may be obtained from model number TD-15-05B-OPT-P90-MED.

In certain embodiments, providing (chemical or structural) coatings or surface modifications to the opening plates to improve microfluidic properties and render the surfaces hydrophilic or hydrophobic or antibacterial. It may be desirable.

In certain embodiments of the present disclosure, an opening plate formed from a high modulus polymer may be processed to reduce residual stresses that may accumulate in its shape and thickness during film formation and fabrication. For example, annealing of PEEK films is a standard procedure proposed by Victrex (www.victrex.com) to obtain optimized crystals and allow relief of intrinsic stresses. Systems and methods for resolving residual stresses in high modulus polymeric materials not only optimize stability in vibrations of the aperture plate, but also minimize the plastic deformation of the inlet and outlet hole geometries of the nozzle plate during operation. It may also provide an increased yield strength of the opening plate formed from the fields. In this regard, systems and methods to relieve residual stresses in a high modulus polymer opening plate are repeatable of the medicament, and may also ensure consistent delivery and administration of the dose.

In addition, PEEK, due to its desirable mechanical performance under dynamic loads and its resistance to high temperatures, is easily laser micromachined and excimer laser ablation, making it a material suitable for the manufacture of aperture plates. As a non-limiting example, laser excimer treatment of polymer surfaces, particularly PEEK surfaces, may be used in the surface treatment of PEEK aperture plates to improve adhesive bonding of the piezoelectric ceramic to the PEEK aperture plate. (P. Laurens, et al., Int. J. Adhes. (1998) 18). In addition, laser ablation and micromachining of PEEK may be used to form parallel grooves or other surface structures, which may lead to the formation of superhydrophobic regions on selected surface areas of PEEK aperture plates, which may result in drug solution or suspension. It is also possible to suppress wetting of selected areas of this opening plate.

As a non-limiting example, the plurality of pores may be from about 1 μm to about 200 μm, from about 2 μm to about 100 μm, from about 2 μm to about 60 μm, from about 2 μm to about 40 μm, from about 2 μm to about 20 μm, About 2 μm to about 5 μm, about 1 μm to about 2 μm, about 2 μm to about 4 μm, about 10 μm to about 40 μm, about 10 μm to about 20 μm, about 5 μm to about 10 μm, and the like It may be a range of diameters. Moreover, in certain embodiments, various openings on the opening plate may have the same or different sizes or diameters, for example some may have an average diameter in the range of about 1 μm to about 2 μm and others about 2 μm To about 4 μm or about 5 μm to about 10 μm. For example, holes of different sizes target different areas of the pulmonary relationship, e.g. tongue, mouth, pharynx, trachea, upper airways, lower airways, deep lunges ), and combinations of them that can be used to generate droplets within a variable size range.

The aperture plate thickness ranges from about 10 μm to about 300 μm, from about 10 μm to about 200 μm, from about 10 to about 100 μm, from about 25 μm to about 300 μm, from about 25 μm to about 200 μm, from about 25 μm to about 100 μm It may also be in the range of μm or the like. Moreover, the number of openings in the opening plate may range from, for example, about 5 to about 5000, about 50 to about 5000, about 100 to about 5000, about 250 to about 4000, about 500 to about 4000, and the like. In certain embodiments, the number of apertures may be increased or decreased by increasing or decreasing the aperture plate pitch (ie, the distance between the centers of the apertures). In this regard, an increase in packing density, ie, reducing the pitch distance and increasing the number of openings in the opening plate, leads to an increase in the total droplet ejection volume.

In certain implementations, the openings in the opening plate may generally have a cylindrical shape, tapered, conical, or hourglass shape. In certain embodiments, the openings have larger openings on one surface of the opening plate, smaller openings on the opposing surface of the opening plate, and have a generally fluted shape with capillaries in between. It might be. Larger and smaller openings may be oriented towards the fluid inlet or fluid outlet surface of the opening plate, as desired.

In the embodiment shown in FIG. 9 , the opening plate is oriented such that larger openings are oriented towards the fluid inlet and smaller openings are oriented towards the fluid outlet. Without intending to be bound by theory, the opening plate opening shape, capillary length, and fluid viscosity can be optimized to determine the resistance flowing through the opening plate opening and provide efficient ejection of droplets.

Referring to FIG. 9 , the openings in the opening plate include a fluid inlet side opening whose diameter D _en is greater than the diameter D _ex of the fluid outlet side opening. The walls of the fluid inlet chamber are grooved and contoured such that the cross-sectional profile of the inlet cavity forms a curvature radius ( E _c ) equal to the opening plate thickness ( t ) minus the capillary length ( C _L ) as defined by the following equation: Is formed:

E _c = t - C _L

Where the fluid inlet-side pore diameter ( D _en ) is equal to twice the inlet cavity curvature radius, plus the fluid outlet-side pore diameter ( D _ex ) as follows:

D _en = 2( E _c ) + D _ex

In certain embodiments, optimization of the aspect ratio of fluid inlet to fluid outlet diameters, in combination with capillary lengths, allows formation of ejected droplets of fluids with relatively high viscosities.

Any suitable method may be used to make aperture plates and a plurality of apertures in aperture plates, which may be known in the art and may be suitable for the particular material of interest. As an example, micromachining, pressing, laser grinding, LIGA, thermoforming and the like may be used. In particular, laser ablation of polymers is an established process for industrial applications. Excimer laser micromachining is particularly well suited for the fabrication of polymer aperture plates. However, the present disclosure is not so limited and any suitable method may be used.

As described herein, the ejector mechanism of the present disclosure also includes a piezoelectric actuator. Piezoelectric actuators are well known in the art, for example, as electronic components used as sensors, droplet ejectors or micro pumps. When a voltage is applied across the piezoelectric material, the crystal structure of the piezoelectric material is affected so that the piezoelectric material changes shape. When an alternating electric field is applied to the piezoelectric material, the piezoelectric material will vibrate (contract and expand) at the frequency of the applied signal. This property of piezoelectric materials can be used to produce effective actuators that displace mechanical loads. As voltage is applied to the piezoelectric actuator, the resulting change in shape and size of the piezoelectric material displaces the load.

As described herein, in certain aspects, the piezoelectric actuator causes the opening plate to vibrate, creating vibrations that lead to the formation of a discharged stream of droplets. As an alternating voltage is applied to the electrodes on the surface of the piezoelectric actuator, the opening plate vibrates and a stream of droplets is generated and discharged in a direction away from the fluid reservoir along the openings in the opening plate.

The piezoelectric actuator may be formed of any suitable piezoelectric material or combination of materials. As a non-limiting example, suitable piezoelectric materials include ceramics exhibiting piezoelectric effects such as lead zirconate titanate (PZT), lead titanate (PbTiO2), lead zirconate (PbZrO3), or barium titanate (BaTiO3). do. In addition, the piezoelectric actuator may have any suitable size and shape that may be compatible to vibrate the opening plate. By way of example, a piezoelectric actuator may have a generally annular or ring shape with a central opening that accepts the active area of the opening plate (area with multiple openings) to allow the ejected stream of droplets to pass through the opening plate. have.

In this regard, the use of annular or ring shaped axially symmetric piezoelectric actuators that generate motion in a generally circular substrate plate for various microfluidic applications is well known. A range of operating voltages may be used as a periodic voltage signal applied to various waveforms, for example, sinusoidal, square or other implementations, the direction of the voltage difference being periodically, eg, an oscillation period depending on the resonant frequency of the piezoelectric material. For example, it may be reversed to a range between +15V and -15V, or between peaks from 5V to 250V. In embodiments of the present disclosure, any suitable voltage signal and waveform may be applied to obtain the desired vibration and operation of the aperture plate.

In piezoelectrically operated devices, the frequency and amplitude of the signal driving the piezoelectric actuator has a significant effect on the behavior of the piezoelectric actuator and its displacement. It is also well known that when the piezoelectric element is resonant, the piezoelectric device will not only achieve its maximum displacement of its mechanical load, but also its highest operating efficiency. In addition, various factors can affect the magnitude of displacement of the opening plate. The factors are, for example, the drive signal of the piezoelectric actuator, the selected resonant frequency, and the eigenmode. Other factors include the generation of charge or voltage as a response to applied stress, or, conversely, loss due to piezoelectric material, resulting from its dielectric response to an electric field and its mechanical response to applied stress.

In addition, the electrical and mechanical response of the piezoelectric actuator can also include, for example, the manufacturing method, configuration and dimensions of the piezoelectric actuator, the position and placement of the mechanical mounting onto the aperture plate and droplet delivery device of the piezoelectric actuator, and the piezoelectric electrode size. And the function of mounting.

In another aspect of the present disclosure, the reservoir may be configured to include an internal flexible drug ampoule that provides an airtight drug container. Referring to FIG. 13 , a flexible drug ampoule 1302 packaged within the hard shell structure 1304 , a screw closure 1306A design (illustrated), a snap-in design or other alternative closure system (not shown) An exemplary reservoir 110 is shown that may include a lid closure 1306 that may be, and an ejector mechanism housing 104A . The reservoir with the flexible drug ampoule also provides a foil lid ( 1308 ), a rigid structure that supports the flexible ampoule, as well as a retainer ring ( 1310 ) that provides a slot for housing the O-ring ( 1312 ). Included, the O-ring prevents leakage once the foil reading 1308 is perforated to release its contents. In certain embodiments, the hard shell structure 1302 is one or more perforated elements that, once the reservoir 110 is placed at a location on the base of the droplet delivery device, are rotated or otherwise placed at a location that pierces the foil reading 1308 . It may also include (not shown). Once the foil reading 1308 is perforated, fluid in the flexible drug ampoule 1302 can be drained into the ejector mechanism.

According to embodiments of the present disclosure, the flexible drug ampoule may be formed using existing form-fill-seal processes. Medical film materials available for its structure are shown below and mainly include micro-thickness (eg, 2-4 mil), low density polyethylene films.

Manufacturer product name description Dow Chemical Company LDPE 91003 Health+ and LDPE 91020 Health Low density polyethylene film Lionel Basel Industries Purel PE 3420F Low density polyethylene film Borealis Group Bormede LE6609-PH Steam sterilizable polyethylene (over 110C) Alkan Packaging Farmer's Packaging I&C. Pouch laminate product code 92036 High barrier leading coextrusion composites of PET, adhesives, aluminum and polyethylene Texas Technologies SV-300X 3 mil nylon, EVOH, poly COEX SAFC Bioscience BioEase Ethyl vinyl acetate film

In another aspect of the present disclosure, the droplet delivery device may include a surface tension plate disposed proximate the opening plate at the fluid contact side of the opening plate. As described above, the surface tension plate, at least in part, advances and focuses the fluid to the opening plate. More specifically, in certain embodiments, the surface tension plate may be on the fluid contact side of the opening plate to provide an even distribution of fluid from the reservoir to the opening plate. In certain aspects of the present disclosure, as will be described in more detail herein, the distance of the placement of the surface tension plate from the opening plate allows optimization of the performance of the ejector mechanism, as measured by the ejected droplet mass fraction. Without intending to be limited, the surface tension plate may have a grid of perforations or holes of various sizes and configurations, which may have circular, square, hexagonal, triangular or other cross-sectional shapes. In certain embodiments, perforations or holes may be positioned along the periphery, center, or throughout the surface tension plate. Any suitable size and configuration of perforations or holes may be used to achieve the desired hydrostatic pressure and capillary action, as described herein. 14A and 14B show exemplary perforation or hole 1402 configurations of various surface tension plates 1400 of the present disclosure. Any suitable material known in the art for pharmaceutical applications may be used so as not to interact with components of the fluid or droplet delivery device to be delivered. Pharmaceutically inert polymers known in the art for these purposes may be used, for example polyethylenes and nylons.

In certain embodiments, as illustrated in FIGS. 2A and 2B , the surface tension plate may be positioned close to and behind the opening plate, generally on the fluid contact side of the opening plate. In addition, in certain embodiments, a surface tension plate may be included as a component of a combination reservoir/discharger mechanism module.

Without intending to be bound by theory, the surface tension plate generates a constant voltage behind the opening plate whose size depends on the spacing between the surface tension plate and the opening plate. For example, the constant voltage exerted by the fluid increases as the gap between the surface tension plate and the opening plate decreases. Moreover, as the surface tension plate distance from the opening plate decreases, there is an increase in the constant voltage that appears as a capillary rise in the fluid between the surface tension plate and the opening plate. In this way, the placement of the surface tension plate on the fluid contact side of the opening plate can help provide a constant supply of fluid to the active area of the opening plate, regardless of the orientation of the inhaler device.

Referring to Fig. 15B , the ratio of the ejected droplet mass as ml/min is measured gravimetrically by weighing the filled reservoir before and after operation. The diagram displayed in FIG. 15B is generated using an ejector mechanism comprising a surface tension plate 1400 having perforations 1402 configured as shown in FIG . 15A and a dome-shaped opening plate (not shown). (5) Averages of 2.2 second operations (sprays). The effect of the polymer composition of the surface tension plate on the ejector mechanism performance was also tested. Surface tension plates were formed using nylon 6 or acrylonitrile butadiene styrene (ABS) copolymer. These compositions were selected to investigate the effect of critical surface tension, water contact angle, and spacing between the surface tension plate and the opening plate, on the ejector mechanism spray performance.

material Critical surface tension (dynes/cm) Water contact angle (degree) Nylon 6 43.9 62.6 ABS 38.5 80.9

As illustrated in FIG . 15B , surface tension plates made of nylon 6 showed an unexpected increase in droplet mass ratio when placed 1.5 mm away from the dome-shaped opening plate, compared to surface tension plates made of ABS. The droplet delivery devices of this disclosure are not so limited, based on the surface energy differences between the constituent materials, as well as the inverse relationship between the hydrostatic forces and the distance between the surface tension plate and the opening plate; Surface tension plate distances greater than about 2 mm may not provide sufficient capillary action or hydrostatic force to ensure a constant supply of fluid to the opening plate. As such, in certain embodiments, the surface tension plate is within about 2 mm of the opening plate, within about 1.9 mm of the opening plate, within about 1.8 mm of the opening plate, within about 1.7 mm of the opening plate, and around 1.6 of the opening plate Within ㎜, within about 1.5 mm of the opening plate, within about 1.4 mm of the opening plate, within about 1.3 mm of the opening plate, within about 1.2 mm of the opening plate, within about 1.1 mm of the opening plate, within about 1 mm of the opening plate It may be disposed on the back.

In other embodiments of the present disclosure, the droplet delivery device may include two or more, three or more, or four or more reservoirs, such as multiple or dual reservoir configurations. In certain embodiments, multiple or dual reservoirs may be a combination multiple or dual reservoir/discharger module configuration, which may be removable and/or disposable. Multiple or dual reservoirs can deliver multiple medications, flavors, or combinations thereof for multiple drug therapy.

In certain aspects, these systems and methods provide a multiple or dual reservoir configuration that can deliver multiple medications prescribed to a patient and may be delivered through the same device. This may be particularly useful for subjects taking multiple medications for multiple indications, or requiring multiple medications for the same indication. According to the present disclosure, a droplet delivery device may be programmed to administer a suitable medicament in an appropriate dosage according to an appropriate dosing schedule, eg, based on barcode or embedded chip information programmed in a pharmacy.

As a non-limiting example, FIGS. 16A and 16B show an exemplary combination dual reservoir/discharger mechanism module and droplet delivery device according to one embodiment of the present disclosure. 16B , the droplet delivery device 1600 includes a device dual base 1602 (including a disposable mouthpiece and a disposable or reusable electronics unit) and a dual reservoir/discharger mechanism module 1604 in combination. do. Combination dual reservoir/discharger mechanism module 1604 provides surface tension plate 1606 , opening plate 1608 , piezoelectric actuator 1610 , optional barcode or embedded chip (e.g. dosing instructions, drug identification, etc.) ), and module insertion guide 1614, shown in more detail in FIG. 16A . As illustrated, each dual reservoir/discharger mechanism module is generally composed of similar components.

More specifically, the combination dual reservoir/discharger mechanism module may have opening plates that are capable of generating ejected droplets with similar droplet size distributions that are similar in design and target similar regions of the lung airways. Alternatively, the use of multiple medications or multiple medications may require delivery of medications to different areas of the lung airways. Under these circumstances, each reservoir of the dual reservoir/discharger mechanism module has different opening configurations (eg, different inlet and/or outlet opening sizes) to deliver different droplet size distributions targeting different areas of the lung airways. , Openings, etc.).

In other embodiments, the present disclosure provides a number of pharmaceuticals, flavorings, wherein the opening plate may include openings with multiple size configurations (eg, different inlet and/or outlet opening sizes, spacings, etc.). Also provided is a single or dual disposable/reusable drug reservoir/dispenser module capable of delivering either, or combinations thereof, for multidrug therapy. Opening plates with openings with multiple size configurations target droplets of different size distributions, thereby targeting different areas of the lung airways. Although multiple size hole combinations are possible, by way of non-limiting example, pores of various combinations and densities are, for example, about 1 μm, about 1 μm, about 3 μm, about 4 μm, about 10 μm, about 15 μm, about 20 μm. , About 30 μm, about 40 μm, etc.

As a non-limiting example, one opening may have an average exit diameter of 4 μm, and an octagonal array of eight larger openings has an average exit diameter of 20 μm. In this way, the opening plate may deliver both larger droplets (about 20 μm diameter) as well as smaller droplets (about 4 μm diameter), which can target different areas of the lung airways, eg For example, you can deliver fragrances to your throat and medicines to deep alveolar passages simultaneously.

Another aspect of the present disclosure, as described herein, excludes larger droplets (with MMAD greater than about 5 μm) from aerosol smoke by filtering them out by their higher inertia and momentum (herein Provides droplet delivery device configurations and methods for increasing the respirable dose of an ejected stream of droplets (referred to as “inertial filtering”). When droplet particles with MMAD greater than 5 μm are generated, their increased inertia mass may provide a means to exclude these larger particles from the airflow by deposition onto the mouthpiece of the droplet delivery device. . This inertial filter effect of the drug delivery device of the present disclosure further increases the respirable dose provided by the device, thus providing improved targeted drug delivery to the desired areas of the airways during use.

Without intending to be bound by theory, aerosol droplets have an initial momentum large enough to be carried by droplet smoke coming from the opening plate. As the gas stream flows around the object in its path and changes direction, suspended particles tend to continue moving in their original direction due to their inertia. However, droplets with MMAD greater than 5 μm generally have a momentum large enough to deposit on the sidewalls of the mouthpiece tube (due to their inertial mass), instead of being deflected and carried into the air stream.

Inertial mass is a measure of an object's resistance to acceleration when a force is applied. It is determined by applying a force to an object and measuring the acceleration resulting from that force. When an object with a small inertial mass is acted by the same force, it will accelerate more than an object with a large inertial mass.

To determine the inertial mass of the droplet particles, the force of F Newton is applied to the object, and the acceleration in m/s ² units is measured. Inertial mass (m) is the force per acceleration in kilograms. The inertia force, as the name implies, is the force due to the momentum of the droplets. This is usually expressed by the term (ρv)v in the momentum equation. So, the denser the fluid, and the greater the velocity of the fluid, the more momentum (inertia) the fluid has.

17A and 17B , FIG. 17A illustrates a recorded negative image of a stream of droplets generated by a droplet delivery device similar to that of FIGS. 2A and 2B. The image provides empirical evidence for the mechanism of generating entrained air from the ejected droplets as a result of the combined momentum transfer from the droplets to the surrounding air and the large specific surface area of droplets of 5 μm or less in diameter. Region 1 represents the region of laminar flow, while region 2 is the region of turbulence due to the production of splash entrained air. 17B shows inertial filtering provided by an exemplary droplet delivery device of the present disclosure that filters out larger droplets from aerosol smoke. The droplets undergo a 90 degree change in the spray direction (4, 5) and are swept by the airflow (3) through the laminar flow element prior to inhalation into the lung airway as the droplets exit the ejector mechanism. Larger droplets 6 above 5 μm are deposited on the sidewalls of the mouthpiece tube via inertial filtering.

In certain embodiments, larger droplets may be allowed to pass through the droplet delivery device within the influence of inertial filtering or with varying effects of inertial filtering. For example, the inlet airflow velocity may be increased (eg, through the use of a mini-fan described herein) and so larger droplet particles may be carried into the lung airways. Alternatively, the exit angle of the mouthpiece tube may be varied (increased or reduced) to allow deposition of droplets of varying sizes on the sidewalls of the mouthpiece. By way of example, referring to FIGS. 17C and 17D , if the angle of the mouthpiece is changed, larger or smaller droplets will collide or pass through the mouthpiece with or without impacting the sidewalls of the mouthpiece. . 17C shows one embodiment with a standard 90 degree rotation, while FIG. 17D shows a rotation greater than 90 degrees. The embodiment of FIG. 17D can allow droplets with slightly larger diameter to pass through without impacting the sidewalls of the mouthpiece.

In another aspect of the present disclosure, in certain embodiments, droplet delivery devices provide various automation, monitoring and diagnostic functions. As an example, as described above, device operation may be provided by automatic subject breathing operation. In addition, in certain embodiments, the device may provide automatic spray verification, to ensure that the device causes proper droplet generation and provides proper dosing to the object. In this regard, the droplet delivery device may be provided with one or more sensors that facilitate this function.

More specifically, in certain embodiments, the droplet delivery device may provide automatic spray verification through LED and photodetector mechanisms. 2A-2C , an infrared transmitter ( eg , IR LED, or UV LED <280 nm LED) 126 and an infrared or UV (UV with <280 nm cutoff) photodetector 124 detect the smoke of the droplets It can also be used for spray detection and verification by being mounted along the droplet ejection side of a device that transmits an infrared or UV beam or pulse. The IR or UV signal can be used to interact with the aerosol smoke, verify that the stream of droplets has been discharged, as well as provide a measure of the corresponding ejected dose of the medicament. Examples are 275 with a GaN photodetector for aerosol spray verification in infrared 850 nm emitters (MTE2087 series) with narrow viewing angles of 8, 10 and 12 degrees or in the solar blind region of spectra nm UV LEDs. Alternatively, in some applications, sub 280 nm LEDs (eg, 260 nm LEDs) can be used to disinfect the spacer tube 128 .

As an example, the concentration of the medicament in the discharged fluid may be made according to the Beer's Law equation (absorbance = e L c), where e is a constant associated with a particular compound or formulation. Molar absorption coefficient (or molar absorption coefficient), L is the path length or distance between the LED emitter and the photodetector, and c is the concentration of the solution. This embodiment can be used for means and methods to provide a measure of drug concentration, verify, monitor patient compliance, as well as detect successful delivery of a drug product.

18A and 18B , including LEDs 126 and photodetectors 124 (see FIGS. 2A-2C ) and (FIG. 18A) deep red LEDs (650nm) and/or (FIG. 18B) Results are shown from exemplary droplet delivery devices enabled with automatic spray verification using an IR LED (850 nm) laser. The exact generation of the stream of droplets may be confirmed by aerosol smoke measurement. As a non-limiting example, aerosol smoke measurement may be implemented at locations in the device mouthpiece tube between the outlet end of the mouthpiece and the ejector mechanism, either across the front face of the ejector mechanism, or in both positions. . Aerosol smoke is optically transmitted through light transmission across the diameter of the mouthpiece for absorption measurement, or by scattering with a photodetector at 90 degrees for optical illumination so that scattering from the aerosol smoke increases the light received by the photodetector. It may be measured.

In still other embodiments, spray verification and dosage verification may be accomplished by formulating a fluid/drug to include a compound that fluoresces (or the fluid/drug may naturally fluoresce). Upon delivery of the stream of droplets, fluorescence may be measured using standard optical means. The light source used for the measurement may be modulated to minimize the influence of external light. When the optical path is modulated to be parallel to the aperture plate and directly across it, the occurrence of droplets by the aperture plate may be measured directly. This direct measurement can allow direct confirmation that the opening plate is ready and working properly. When mounted between the droplet outlet and the opening plate, aerosol smoke may be monitored as it passes through the droplet delivery device. The optical means may be any conventional LED with a relatively narrow beam and a half-angle of less than 20 degrees. Alternatively, a laser diode may be used to create a very narrow, collimated beam that is reflected from individual droplets. Various wavelengths from near UV to near IR have been used to successfully measure aerosol smoke absorption in transmission mode. By using very short wavelength LEDs less than 280 nm, interference from sunlight or other existing light sources can be avoided by placing a filter on the detector that attenuates wavelengths longer than 275 nm. Likewise, if a fluorescent material is added to the fluid/drug, an optical bandpass filter may be placed in front of the detector to avoid interference from excitation light or external light. Restriction of ambient light may also be accomplished by using vanes or shades as part of the air restriction opening between the device and ambient air.

In another aspect of the present disclosure, the droplet delivery device breathes, such as a mechanical respiratory or portable Continuous Positive Airway Pressure (CPAP) machine, to provide respiratory assist airflow to the in-line dosing of therapeutic agents. It may also be used in conjunction with auxiliary mechanisms or integrated with such a CPAP machine.

For example, mechanical respirators with endo-tracheal (ET) tubes are used to block secretions from entering the lungs of an unconscious patient and/or blocking the patient from breathing secretions. The ET tube is an inflatable balloon that seals the inside of the trachea just below the larynx. However, common undesirable side effects resulting from the use of mechanical respirators include ventilator-assisted pneumonia (VAP), which occurs in about one third of patients who have been inhaling the respirators for more than 48 hours. . As a result, VAP is associated with high morbidity (20% to 30%) and increased health care systems costs. (Fernando, et al., Nebulized antibiotics for ventilation-associated pneumonia: a systematic review and meta-analysis. Critical Care 19:150 2015).

Tobramycin administration via the pulmonary route, where nebulizers are commonly used to deliver antibiotics through the generation of a continuous stream of droplets into the respiratory airflow, is generally considered superior to intravenous administration to treat VAP. The main advantage of inhalation over antibiotics administered orally or intravenously is the ability to deliver higher concentrations of antibiotics directly into the lungs. However, the continuous production of nebulizer mist provides inaccurate dosing that cannot be verified between inhalation and exhalation cycles.

As such, with reference to FIG. 19 , one embodiment of the present disclosure is provided in which the droplet delivery device 1902 is disposed in series with the respiratory 1900 (eg, GE Carescape R860). The droplet delivery device 1902 generates a stream of droplets as described herein, the stream of droplets comprising a therapeutic agent such as tobramycin entering the respiratory airflow near the patient end of the endotracheal tube 1904 . do. 19 shows an example of a standalone device 1902 operating as a respirator 1900 . The respirator 1900 supplies the intake air stream 1900A and exhales in separate tubes that merge into a single endotracheal tube 1904 close to the patient to minimize mixing and dead volume of inhalations and exhalations. The air stream 1900B is removed. The droplet delivery device 1902 may be disposed near the patient end of the endotracheal tube 1904 to minimize the loss of droplets that may adhere to the tube sidewall. The patient end of the endotracheal tube 1904 is placed within the patient's throat and held in place with a balloon (not shown) near the end of the tube.

Operation of the droplet delivery device is initiated at the start of the suction cycle. The droplet delivery device may be battery powered and self-starting, breathing activated or connected to electronics that are part of the respiratory tract. The system may be configured such that the dosing frequency and duration may be set within either the respirator or device. Likewise, the timing and duration of droplet ejection can be determined by the device or initiated by the respiratory system. For example, the device may be programmed to dose once every 10 breaths in succession or perhaps once every 10 minutes for 1/2 second. The device may operate in a self-contained manner or may deliver timings and flow rates of medications by direct electrical connection to the respirator or via Bluetooth or similar wireless protocol.

Another aspect of the present disclosure provides a system that may also be used with existing portable CPAP machines to deliver therapeutic agents, eg, when continuous or periodic dosing during the night is valuable. In other embodiments, droplet delivery devices of the present disclosure may be used in connection with a portable CPAP machine that prevents and processes cardiac events during sleep.

CPAP machines typically use a mask to provide positive air pressure to the patient during sleep. Applications of droplet delivery devices in conjunction with CPAP machines are diseases, conditions, or disorders such as pneumonia, atrial fibrillation, myocardial infarction, or any disease, condition, or disorder in which continuous or periodic nighttime delivery of a drug is desired. For the outpatient treatment of their patients, an efficient method for continuous dosing of therapeutic agents such as antibiotics, cardiac medicines, etc. may be provided.

In sleep apnea (SA) there are periods of non-breathing and associated reductions in blood oxygen levels. Not surprisingly, heart failure or "heart attacks" are associated with sleep apnea. This association is believed to be due to both the stress on the heart associated with low oxygen levels and the increased stress on the heart as the body requires increased blood pressure and heart output from the heart. In addition, the risk of sleep apnea increased in older adults and overweight adults. Therefore, people with SA have a higher risk of heart attack than the general population, because SA stresses the heart and the risk factors associated with SA are very similar to the risk factors for heart attack.

The New England Journal of 2016 published a four-year study of the effects of CPAP on 2700 people with sleep apnea, and CPAP significantly reduced snoring and daytime sleepiness, and health-related life and mood quality. It was found that it improved. (R. Doug McEvoy, et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea, N. ENGL. J. MED . 375;10 nejm.org September 8, 2016). However, the use of CPAP does not significantly reduce the number of cardiac events. The paper noted that "obstructive sleep apnea is a common condition among patients with cardiovascular disease, affecting 40 to 60% of these patients."

Many of these cardiac events can be reduced by administration of appropriate medications. For example, beta blockers, such as metoprolol, can reduce the effects of atrial fibrillation and myocardial infarction to a degree sufficient to prevent death from these symptoms.

In certain aspects of the present disclosure, the need to reduce negative cardiac events in a population of people using CPAP devices is addressed by detecting the presence of the event and administering an improved drug through delivery of the lungs. Specifically, cardiac events may be detected by existing available means of detecting and evaluating cardiac conditions. These are heart rate monitors (such as electrical sensors held in place by elastic bands across the chest or optical monitoring on the earlobe, finger or wrist), automated blood pressure cuffs, or blood oxygenation on the finger or ear Saturation monitors). When the monitor detects a negative condition, a specific dose of the appropriate drug is administered through the CPAP tube or mask by the droplet delivery device of the present disclosure, such that the drug is inhaled and carried to the blood stream through deep inhalation into the lungs. . Pulmonary administration is optimized by both the generation of droplets of size less than 5 microns and the delivery of droplets at the beginning of the inhalation cycle.

Referring to FIG. 20 , a schematic representation and example for use of the system 2000 includes a droplet delivery device 2002 of the present disclosure and a CPAP machine 2004 for supporting cardiac events during sleep. In certain aspects of the present disclosure described herein, the patient is shown sleeping with the CPAP mask 2006 in place and pressurized air is delivered by the CPAP machine 2004 to the mask 2006 . The heart condition is monitored by optical measurement of the heartbeat on one of the fingers, toes, earlobe or wrist (not shown). The droplet delivery device 2002 may be disposed in line with the tube 2008 between the CPAP machine 2004 and the CPAP mask 2006 , or alternatively may be placed at the airflow inlet of the CPAP mask 2006 (shown). Not). Respiration is monitored by airflow measurement in a tube ( 2008 ) from CPAP machine ( 2004 ) to CPAP mask ( 2006 ). The amount of airflow and direction can be measured by measuring the pressure on either side of the screen, adding some airflow limitation. Typically there will be a constant amount of airflow that increases the flow rate upon intake. The controller detects an abnormal cardiac condition, such as an increase in atrial fibrillation, and triggers the release of droplets of antiarrhythmic drug at the start of an inhalation cycle as detected by airflow in the CPAP feed tube. Information may be recorded and stored on the patient's smartphone 2010 , and if a heart event is detected (eg, transmitted via Bluetooth or other wireless communication method), various alerts may be triggered, if desired. In addition, the patient's condition and drug medications may be monitored through a smartphone app to provide an accurate record of the patient's condition to the patient and his healthcare provider.

Sleep apnea, the use of mechanical respirators, or other diseases commonly associated with CPAP machines also benefit from a system that non-invasively monitors the patient's condition and provides pulmonary administration of appropriately improved medications through the droplet delivery device of the present disclosure. It might be. For example, people with diabetes often worry that low blood sugar from some insulin overdosing leads to loss of consciousness. In this case, abnormally low heart rate, breathing or blood pressure can be detected and sugar or insulin administered via droplets to the lungs.

Examples

Example A: Automatic breathing operation

1B-1E , droplet delivery device configurations of the present disclosure are provided, including various sensor orientations that provide automatic breathing operation and automatic spray verification of the ejector mechanism. The sensors trigger the operation of the aerosol smoke during the peak period of the patient's inhalation cycle. Adjustment of the peak duration of the patient's inhalation in certain embodiments may ensure optimal deposition of aerosol smoke and associated drug delivery into the patient's lung airways. Although multiple arrangements are possible, FIG. 1B shows an exemplary sensor configuration. The SDPx series (SDP31 or SDP32 pressure sensors) from Sensirion (www.sensirion.com) may be used.

Example B: Droplet size distribution

Droplet size distribution and related functions were evaluated for exemplary droplet delivery devices of the present disclosure, including Anderson Cascade impactor testing, total drug mass output rates, total drug respirable mass, delivery efficiencies and reproducibility. 21A-21F provide a summary of test results.

Test design

Studies were conducted at ARE Labs, Inc. to evaluate the aerosol properties and delivered dose of albuterol sulfate using a Pneuma ™ inhaler device. The study was designed to evaluate the device performance of a single Pneuma™ inhaler. A series of three individual tests were performed with a new disposable drug cartridge for each test. The testing platform is a calibrated AALBORG model GFM47 mass flow meter (AALBORG Instruments and Controls; Orangeburg, NY) equipped with an 8-stage nonviable Anderson Cascade Impactor calibrated for flow rate measurement. Fisher Fisher Scientific (Wolsom, MA). A valved gas rotary vane vacuum pump (Gast Manufacturing; Benton Harbor, MI) was used.

A droplet delivery device of the present disclosure similar to that shown in FIGS. 2A-2C was tested three times with a fresh reservoir filled with 750 μl of 5000 mg/ml albuterol sulfate for each of the tests performed three (3) times. Fractions of drug (100 μl) were extracted from a stock preparation solution of albuterol sulfate using a calibrated micropipette, diluted in mobile phase and analyzed via HPLC for drug concentration. At the end of each test, the mouthpiece was rinsed with the mobile phase to determine the mass fraction of the unbreathable aerosolized drug captured in the mouthpiece through inertial filtering and collected for HPLC analysis. Following each test, impactor stage samples were extracted, recovered in solvent and used with Dionex Ultimate 3000 nano-HPLC (Thermo Scientific, Sunnyvale, CA) with UV detection. It was analyzed for active pharmaceutical ingredient (API).

The cascade impactor testing procedure involved fitting the mouthpiece into the impactor USP throat with a mouthpiece connection seal. The vacuum pump supplying sample air flow to the cascade impactor was turned on and the pump control valves were adjusted to supply a total flow of 28.3 L/min through the impactor and inhaler body during aerosol tests.

At the start of each test, a new reservoir was filled with 750 μl of stock stock solution of albuterol sulfate using a calibrated micropipette. The device was connected to the impactor USB throat, turned on, and operated 10 (10) times for each test. At the end of the test period, the device, impactor, and dilution air sources were turned off. The mouthpiece was rinsed to extract the drug, and all stages of the Cascade Impactor were rinsed with any amount of suitable solvent (HPLC mobile phase). The extracted samples were placed in labeled sterile HPLC vials, capped, and analyzed for drug content using UV detection via HPLC. The mouthpiece was analyzed by HPLC for drug content to measure the mouthpiece drug deposition over the entirety of the residual drug was extracted and collected on the impactor stages.

All system flow rates and impactor sample flows were monitored throughout each test period. Following each test, impactor slides were placed in labeled sterile Petri dishes, and drug was extracted using 2 ml of mobile phase applied with a calibrated micropipette at the impactor stages. All extracted samples from the mouthpiece and impactor were placed in labeled sterile amber HPLC sample vials and stored refrigerated to approximately 2°C until HPLC analysis.

Impactor collection stages for all tests were rinsed with DI water and ethanol and air dried prior to each inhaler test trial to avoid contamination. A new inhaler drug cartridge was used for each of the three separate tests.

Drug analysis

All drug content analyzes were performed using a Dionex UVD-3000 multi-wavelength UV/VIS detector equipped with a Dionex Ultimate 3000 nano-HPLC using a micro flow cell (75 μm x 10 mm path length, total analytical volume 44.2 nl). Using. The column used for the albuterol sulfate was a Phenomenex Luna (0.3 mm ID x 150 mm) C18, 100 A (USP L1) column with a column flow rate of 6 μl/min at a nominal pressure of 186 bar. The total HPLC run time was 6 minutes per sample with approximately 5 minutes of flush between each sample. Sample injection was performed with a 1 μl sample loop in full loop injection mode. Detection was done with UV at 276 nm against albuterol sulfate.

HPLC methods and standards

The US Pharmacopoeia monograph USP29nf24s_m1218 was followed as a reference method for the analysis of albuterol sulfate. In short, the method includes a mobile phase; Dilution of the appropriate formulation of albuterol sulfate in 60% buffer and 40% HPLC grade methanol (Acros Organics) was involved. The buffer formulation had 1.13gr of 1-hexanesulfonic acid sodium (Alfa Aesar) in 1200 ml of water and reverse osmosis filtered dehydration with 2 ml glacial acetic acid (Across Organics) added. Contains ionized water. The mobile phase solution was mixed and filtered through a 0.45um filter membrane. The final mobile phase is a 60:40 dilution of buffer: MEOH.

Statistical analysis

The mean and standard deviation were calculated for all three test sets for each of the following components: inhaler filled drug, total delivered dose, coarse particle dose, coarse particle fraction, respirable particle dose, respirable particle Fraction, fine particle dosage, fine particle fraction, aerosol MMAD and GSD. The number of trials were provided with 95% confidence levels for all data sets.

Results

The table below provides a summary of the mass fraction of the droplets collected on each droplet size stage of Anderson Cascade impactor testing (Albuterol, 0.5%, Anderson Cascade, 28.3 lpm, 10 runs). As shown, droplets greater than 75% have an average diameter of less than about 5 μm, and droplets greater than 70% have an average diameter of less than about 4 μm.

The table below provides results based on the possible areas of droplet impact in the mouthpiece/neck/rough, respirable droplets, and microdroplets (albuterol, 0.5%, Anderson Cascade, 28.3 lpm, 10 runs). Provides an alternative format for a summary of cascade impactor testing results.

21A-21D illustrate the same data in various compilations. 21A shows percentages of droplets deposited into mouthpiece, throat, rough, respirable, and fine. FIG. 21B shows MMAD and GSD for all trials, and average (3 cartridges, 10 runs per cartridge; albuterol, 0.5%, 28.3 lpm; total 30 runs). 21C-1 and 21C-2 illustrate cumulative diagrams of the aerodynamic size distribution of data from FIG. 21B . Figure 21D illustrates throat, coarse, respirable and fine particle fractions, and average (3 cartridges, 10 operations per cartridge; albuterol, 0.5%, 28.3 lpm; 30 operations in total) in each trial. .

Example C: Comparative droplet generation vs. Combivent® Respimat® and Proair® HFA

Two recognized devices: Combivent® Respimat® inhaler (CT, Ridgefield's Boehringer Ingelheim Pharmaceuticals Inc.) and PROAIR® HFA (PA State, Fraser's Teva Repertory) An in vitro study was conducted in which a droplet delivery device of the present disclosure was evaluated and compared with Teva Respiratory, LLC. Initially, with reference to FIGS. 22A and 22B , a comparison of aerosol smoke generated from the droplet delivery device (test device) and Respimat Softmist® inhaler of the present disclosure is illustrated. In FIG. 22A, the aerosol smoke produced by the test device has two distinct flow patterns associated with laminar flow (1) and turbulent flow (2). As previously mentioned herein, the formation of turbulence and eddy currents is created when droplets have MMAD diameters of less than 5 μm and leads to the production of entrained air. In contrast, in FIG. 22B, the smoke formed by the Respimat Softmist® inhaler indicates that aerosol smoke characterized by droplets with high velocities and a wide range of droplet sizes has high momentum and kinetic energy.

Devices were tested with dosing sulfate albuterol aerosol size distribution and mass transfer properties. As described herein, the droplet delivery device of the present disclosure is a breathing actuated piezoelectric device having a removable and replaceable reservoir. In this example, the reservoir is designed to contain a therapeutic inhalation drug volume that provides 100 to 200 breath-operated doses per use. The accredited device Combivent Respimat is a propellant-free, piston-operated, multidose metered inhaler, while the ProAir HFA device is a CFC-free, propellant-based metered dose inhale. to be.

A single test device body and three (3) reservoir/discharger mechanism modules were tested. All accredited devices were tested three times, for a total of nine (9) cascade impactor tests. The devices of this disclosure were tested three times with a new drug reservoir filled with 750 μl 0.5% albuterol sulfate for each of the three (3) tests.

Particle size distributions were measured using Anderson Cascade Impactor (ACI) sampling at a constant 28.3 lpm during each test. The Anderson Cascade Impactor Test is as described in Example B above, and can be used to determine coarse particle mass, coarse particle fraction, respirable particle mass, respirable particle fraction, fine particle mass, and fine particle fraction of test aerosols. . ACI data can also be used to calculate the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) of the aerosol size distribution. Droplet classifications are defined as follows: coarse particle fraction >4.7 um; Respirable fraction, 0.4 to 4.7 um; Fine particle fraction, <0.4 um.

Recognized Combivent® Respimat® inhalers were tested using Combivent® Respimat® cartridges containing 100 mcg albuterol and 20 mcg ipratropium bromide equivalent to a 120 mcg dose of albuterol sulfate delivery per operation. Although a recognized PROAIR® HFA inhaler was evaluated with cartridges containing 108 mcg albuterol sulfate equivalent to a 90 mcg delivery dose per operation, the droplet delivery device of the present disclosure was delivered at a delivery dose of 85 mcg per operation and 0.5% albuterol. It was evaluated using an equivalent concentration of 5000 ug/ml albuterol sulfate.

The results of the cascade impactor test tests for each inhaler tested three times for albuterol sulfate are as follows ( FIGS. 23A and 23B ):

Test device for dosing albuterol sulfate, 1.93±0.11, Combivent® Respimat®, 1.75±0.19, and mean MMAD for PROAIR® HFA 2.65±0.05 μm.

Test device: 1.96 ± 0.16, Combivent® Respimat®, 2.79 ± 0.25, and PROAIR® HFA, mean GSD for 1.48 ± 0.02.

A summary and comparison of the cascade impactor testing of the test device, Combivent Respimat® and Proair® HFA inhalers is shown in the tables below and in FIGS. 23A and 23B . These data are tested It is shown that the device provides the highest respirable particle fraction for the devices tested with the following mean±standard deviation ( FIG. 23B ):

68.7% ± 3.2% for test devices,

Combivent® Respimat®, 57.3% ± 10.5, and

PROAIR® HFA, 65.2% ± 2.4%.

Example D: Clinical study-Albuterol sulfate and ipratropium bromide

Using the exemplary ejector device (test device) of the present disclosure, comparing the acute bronchodilator effect of a test device with albuterol sulfate and ipratropium bromide for no treatment in a group of patients with chronic obstructive pulmonary disease Cross clinical trials were conducted.

Up to 75 patients with COPD will be enrolled. For study eligibility, subjects at Visit 1 were: 1) previously diagnosed with COPD; 2) has a smoking history of at least 10 pack year; 3) one or more inhaled bronchodilators are prescribed; 4) FBR1 ≥ 25% of the predicted normal value and FEV1 <70% of the predicted normal value after bronchodilator should be met using appropriate reference equations.

The study is a cross-, single-center, 1-day lung function study that measures the acute bronchodilatory effects of standard doses of albuterol sulfate and ipratropium bromide using a test device of the present disclosure in a group of COPD patients.

Subjects may go through a screening period of up to 1 week. If the patient is not using long-acting beta agonists or long-acting muscarinic antagonists and did not use short-acting bronchodilators in the previous 6 hours, no washout period is required and can proceed immediately to Visit 2. have. If the subject is using long acting beta agonists, the subject will be washed for 48 hours. If the subject is using long-acting muscarinic antagonists, the duration of the drug wash will be one week. During the drug wash period, subjects were inhaled corticosteroids (ICS), short acting beta agonists (SABA), short acting muscarinic antagonists (SAMA), It will be acceptable to continue to use leukotriene inhibitors, and phosphodiesterase 4 inhibitors. Subjects experiencing COPD exacerbations during the drug wash period will be excluded from the trial. Subjects who successfully complete the screening period will be included in the trial.

As described herein, test devices include piezoelectrically operated ejector mechanisms in which the reservoir is integrated. The reservoir is mounted in the device housing. The device housing has two areas: 1) mouthpiece tube and 2) handle. The patient breathes through the mouthpiece tube to activate the ejector mechanism. The mouthpiece tube can be separated from the housing and sterilized and reused or placed after use by the patient.

The primary efficacy endpoints are for 2 hour periods, i.e., 20 minutes prior to receiving a dose of albuterol sulfate and epratropium bromide using the ejector device of the present disclosure, and albuterol sulfate from the ejector device of the present disclosure. And changes in FEV1 for 20 minutes after receiving a dose of ipratropium bromide. Safe endpoints will include vital signs and changes in FEV1. Statistical analysis will include analysis of changes in FEV1 using T-tests.

Interim results demonstrate that the use of the ejector device of the present disclosure provides a significant bronchodilator effect compared to no treatment. For example, with partial registration, the following average FEV1 readings were obtained:

Time point FEV1 (liters) ^* Reference value 1 1.3733 Baseline 2 (+20 minutes) 1.4133 Treatment 1 (+20 minutes after treatment) 1.6688 Treatment 2 (+60 minutes after treatment) 1.6844 Treatment 3 (+120 minutes after treatment) 1.6522

*The average baseline FEV1 for the group is 1.29 liters. The average change in 20 min FEV1 is 220 cc at p=0.000012. The average change in 60 min FEV1 is 260 cc at p<0.00001. In other words, a 17% improvement at 20 minutes and a 20% improvement at 60 minutes. As shown in the table above, treatment with the ejector device of the present disclosure improved FEV1 by an average of about 260-275 cc. . This improvement is a 1.2 to 2 fold increase in the bronchodilatory effect normally observed using standard passive inhalers with the same dose of active drug.

Example E: Clinical Study-Albuterol Sulfate

Cross comparing the acute bronchodilatory effects of a test device with albuterol sulfate on a ProAir® HFA inhaler in a group of patients with chronic obstructive pulmonary disease (COPD), using an exemplary droplet delivery device (test device) of the present disclosure. Clinical trials were conducted.

Up to 75 patients with COPD will be enrolled. For study eligibility, subjects at Visit 1 were: 1) previously diagnosed with COPD; 2) have a history of smoking at least 10 packs per year; 3) one or more inhaled bronchodilators are prescribed; 4) FEV1 <70% of the predicted normal value or at least 10% lower than the predicted normal value should be satisfied using appropriate reference equations.

It measures the acute bronchodilator effect of standard dose albuterol sulfate using a test device in a group of COPD patients and this is the same drug given as a half dose administered to the accreditation device with the Proair HFA hop inhalation device. Comparing crossover, single centroid, 2-3 day lung function studies.

Subjects may go through a screening period of up to 1 week. If the patient is not using long-acting beta agonists or long-acting muscarinic antagonists and did not use a short-acting bronchodilator in the previous 6 hours, a drug washout period is not required and can proceed immediately to Visit 2. If the subject is using a long acting beta agonist, the subject will be washed for 48 hours. If the subject is using long-acting muscarinic antagonists, the duration of the drug wash may be up to one week. During the drug wash period, subjects continue to use inhaled corticosteroids (ICS), short acting beta agonists (SABA), short acting muscarinic antagonists (SAMA), leukotriene inhibitors, and phosphodiesterase 4 inhibitors. Will be allowed. Subjects experiencing COPD exacerbations during the drug wash period will be excluded from the trial. Subjects who successfully complete the screening period will be included in the trial.

As described herein, test devices include piezoelectrically operated ejector mechanisms in which the reservoir is integrated. The reservoir is mounted in the device housing. The device housing has two areas: 1) mouthpiece tube and 2) handle. The patient breathes through the mouthpiece tube to activate the ejector mechanism. The mouthpiece tube can be separated from the housing and sterilized and reused or placed after use by the patient.

Primary efficacy endpoints included changes in FEV1 during 2 hour periods, i.e., 20 minutes before receiving a dose of albuterol sulfate and 20 minutes after receiving a dose of albuterol sulfate using the test device of the present disclosure. something to do. Safe endpoints will include vital signs and changes in FEV1. Statistical analysis will include analysis of changes in FEV1 using T-tests.

The results provided a significant but slightly improved bronchodilator effect compared to treatment with a double dose using the Proair HFA device, which is a recognized device, and the use of the test device of the present disclosure is significant compared to no treatment. Proves More specifically, there was a statistically significant improvement in FEV1 (120 ml) with a device of 100 microgram dose of albuterol compared to no treatment. In addition, it was unexpectedly confirmed that the average improvement was 11.9 ml more than the improvement seen with twice the dose of 200 micrograms using a recognized device Pro HFA inhaler. In this regard, the test device of the present disclosure was able to achieve similar but slightly improved clinical efficacy at half the dose of the accreditation device. The test device was able to deliver condensed doses of COPD medication and provide meaningful therapeutic efficacy compared to standard treatment options.

The tables below provide detailed data:

Example F: Delivery of large molecules-local and systemic delivery

Using exemplary droplet delivery devices of the present disclosure, epidermal growth factor receptor (EGFR) monoclonal antibodies, bevacizumab (Avastin), adalimumab (Humira) and etaner Testing is conducted to verify that large molecules, including etanercept (enbrel), are not denatured or degraded by ejection through the device of the present disclosure, and that local pulmonary delivery and/or systemic delivery of the active agent is achieved. do.

Droplet Characterization : To verify droplet generation, as described herein, droplet impactor studies may be performed.

Gel electrophoresis : To determine the stability of the active agent after droplet formation, the generated stream of droplets containing the active agent was collected and the molecular weight of the active agent was verified using gel electrophoresis. Gel electrophoresis has negligible changes in the molecular weight of the post-aerosol activator on the basis of the molecular weight of the control group, i.e., whole EGFR antibodies, bevacizumab, adalimumab, or etanercept, in electrophoretic mobility. Will show The gel will also show that there is no evidence of smaller pieces of protein on the gel, and will further confirm that aerosol production will not cause any remarkable proteolysis. In addition, the gel will show no apparent aggregation of antibody or protein, which is important because many inhalation devices are prone to protein aggregation and thus have been reported to be unsuitable for lung delivery of large macromolecules such as proteins and antibodies.

Size Exclusion Chromatography (SEC) : Alternatively, to determine the stability of the active agent after droplet formation, the resulting stream of droplets containing the active agent may be collected and SEC-HPLIC is random at large molecular aggregation and protein fragment content. It can also be employed to monitor changes. Soluble protein aggregates and protein fragment content can also be calculated by comparing each peak region under the SEC-HPLC curve of the administered protein solutions with controls (solutions remaining in the device reservoir).

Drug solutions for testing include Enbrel (25 mg of ENBREL® single-use prefilled syringes (0.51 mL of etanercept 50 mg/mL solution), insulin (Humalog, 200 units/ml), 3ml quick fence)

ENBREL® (etanercept) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. . The Fc component of etanercept includes the CH2 domain, the CH3 domain and the hinge region, but does not include the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in the Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.

SEC is performed with a Yarra ^™ 3 um SEC-2000 LC column 300 x 7.8 mm, security guard cartridge kit and security guard cartridges GFC-2000, 4 x 3 mm ID. Fifty microliters of Enbrel (4:1) of a syringe (ENBREL® single-use prefilled syringes of 25 mg/0.51 mL of etanercept 50 mg/mL solution) (4:1) (200 mcl of mobile phase buffer solution 4 from the syringe (50 mcl of Enbrel 1 ratio). Fifty microliters of diluted Enbrel was injected and separation was performed at a flow rate of 1.0 ml/min. The mobile phase buffer system is PHOS. BUFF. SALINE. (PBS) solution and 0.025% NaN ₃ , pH 6.8 were included. UV detection was performed at 280 nm.

To calculate and compare the effects of droplet generation through the ejector mechanism of the present disclosure, the total area under the curve of the UV signal at 280 nm relative to the elution time for the controls is compared to aerosolized samples set to 100%. .

Fifty microliters (mcl) of insulin (Humalog, 200 units/ml, 3ml quickfence) is taken directly from the quickpen and injected into the SEC column for analysis while a 200mcl quickpen solution is used to test the device. It is injected directly into the ampoule/cartridge prior to operation and aerosol production. Aerosol collection and SEC are performed in a similar fashion to that for Enbrel analysis and aerosol collection.

0.20 ml Enbrel of either of which the ampoules/cartridges were diluted 4:1 (10 mg/ml) in a ratio of 1 (50 mcl of Enbrel solution from syringe) to 0.025% NaN ₃ 4 (200 mcl) with PBS. ® (50 mg/ml). After 20 operations and aerosolization, about 150 mcl of aerosolized Enbrel solution is recovered and collected in a polypropylene tube located under the ejector mechanism. The control consists of a diluted Enbrel solution, 50 mcl of the solution is injected into the SEC column for analysis.

Insulin solutions from Humalog, 200 units/ml, 3ml quickpen are taken out by syringe and 200 mcl is injected directly into the reservoir/discharger mechanism module and mounted prior to operation on the test device. The aerosol from the test device is collected by placing a 0.5 ml polypropylene test tube directly under the opening plate. Aerosolization of twenty operations resulted in a recovery of about 150 mcl of aerosol insulin spray. Fifty microliters of the collected aerosol spray is injected into the SEC column for analysis, while 50 mcl of Quickpen insulin solution is injected onto the SEC column for control samples.

Results; Enbrel

24A and 24B, SEC chromatographs of aerosolized Enbrel solutions (FIG. 24B) collected from a test device after operation with a 4:1 diluted Enbrel®, (10 mg/ml) control (FIG. 24A) There are. A single major peak is evident in the chromatographs of the aerosolized Enbrel solution with an elution time of about 25 minutes. The tables below compare regions under UV curves for various peaks coming from specified elution times (minutes) for controls and aerosolized Enbrel solutions.

Enbrel Stability Studies: Aerosol Generation Using Test Devices Peak area% Peak 1 (residence time) Peak 2 (residence time) Peak 3 (residence time) Peak 4 (residence time) Peak 5 (residence time) Control 1 2.428 (4.336) 96.676 (4.827) 0.373 (11.628) 0 0 Control 2 3.041 (5.326) 95.909 (5.785) 0.351 (12.605) 0 0 Aerosolized S1 2.796 (5.372) 90.789 ( 5.853 ) 0.424 (12.675) 0.357 (13.051) 5.130 (25.139) Aerosolized S1 3.476 (5.338) 92.112 (5.821 0.361 (12.625) 0.352 (13.020 3.428 (25.082

Peak 4 Peak 5 Aerosolized S1 0.357 5.123 Aerosolized S2 0.352 3.428 Average 0.3545 4.2755 Standard Deviation 0.0035 1.1985

These data indicate that the test device can deliver 95.4% of the structurally unchanged Enbrel after delivering the aerosol dose, whereas only 4.6% of the dose leads to the formation of molecular fragments with elution times of 13 minutes and 25 minutes. The gravimetric analysis was performed by weighing the ampoule filled with Enbrel solution before and after dosing. The average of 5 doses (operations) was analyzed as an average of 4.25 mg +/- 0.15 mg. The total delivered dose of Enbrel per operation is therefore 42.5 mcg per operation. In comparison, the operation of distilled water using the same ampoule was 9.26 mg. The delivery dose was +/- 1.19 mg.

Results; insulin

25A and 25B , SEC of insulin from quickpen (200 U/ml; 34.7 mcg/U; 6.94 mg/ml) as a control ( FIG. 25A ) and aerosolized ones from the test device ( FIG. 25B ) There are chromatographs. About 150 mcl of aerosolized insulin solution were collected from the test device after operation. A single major peak is evident in the chromatograph of the aerosolized insulin solution with an elution time of about 25 minutes. The tables below compare regions under UV curves for various peaks coming from specified elution times for the control groups and aerosolized insulin solutions. Retention times are in minutes.

Insulin Stability Studies: Aerosol Generation Using a Pneuma Inhaler Device Peak area% Peak 1 (residence time) Peak 2 (residence time) Peak 3 (residence time) Control 1 29.926 (10.786) 69.630 (22.603) 0 Aerosolized S1 28.721 (10.823) 67.807 (22.508) 2.797 (25.017) Aerosolized S2 27.881 (10.878) 69.780 (22.726) 2.184 (25.247)

Peak 3 Aerosolized S1 2.797 Aerosolized S2 2.184 Average 2.4905 Standard Deviation 0.4335

These data demonstrate that the test device can deliver 97.5% of the ejected dose of insulin that has not been structurally altered, while 2.5% of the ejected dose forms fragments that elute in ~25 minutes. Was performed by weighing the ampoule filled with insulin solution before and after dosing. The average of 5 doses (operations) was analyzed as an average of 5.01 mg +/- 0.53 mg. The total delivered dose of insulin per operation is therefore 34.8 mcg per operation. Antibody/protein binding assay : The activity of an aerosolized antibody or protein is demonstrated by testing its ability to bind targets on its antigen or cell surface, ie EGFR, TNFα, and the like. Flow cytometry data of cells cultured with either aerosolized or non-aerosolized actives will reflect activity. Specifically, the data will show a shift in fluorescence intensity of cells cultured with a non-aerosolized fluorescently labeled active agent compared to that for untreated cells. A similar shift will be obtained with cells cultured with an aerosolized active agent, which post-aerosolized active agent retains its immune activity and thus retains its ability to bind its target receptor on the cell surface. Suggests

Clinical/in vivo testing : Clinical trials were conducted to evaluate pharmacokinetic data following administration of large molecular active agents, as shown generally in FIGS. 1A-1E, using an exemplary ejector device of the present disclosure. Is performed. pK data will verify that large molecular active agents are successfully administered systemically.

Claims (20)

A piezoelectrically operated droplet delivery device that delivers fluid as a discharged stream of droplets to a subject's disposal relationship,
housing;
A storage tank disposed in the housing or in fluid communication with the housing to receive a volume of fluid;
A discharger mechanism in fluid communication with the reservoir, wherein the discharger mechanism includes a piezoelectric actuator and an opening plate, the opening plate having a plurality of openings formed through its thickness, and the piezoelectric actuator opening the opening plate The ejector mechanism operable to generate an ejected stream of droplets by vibrating at a frequency;
At least one differential pressure sensor located within the housing;
The at least one differential pressure sensor configured to generate a discharged stream of droplets by actuating the ejector mechanism upon sensing a predetermined pressure change in the housing; And
The ejector mechanism configured to generate an ejected stream of the droplets, wherein at least about 70% of the droplets have an average ejection droplet diameter of less than about 5 microns, such that at least about 70 of the mass of the ejected stream of droplets % Is a droplet delivery device comprising the ejector mechanism, which is delivered to the subject's disposal relationship in a breathable range during use. According to claim 1,
And a surface tension plate between the opening plate and the reservoir, wherein the surface tension plate is configured to increase the contact between the volume of fluid and the opening plate. According to claim 2,
The ejector mechanism and the surface tension plate are configured in a parallel orientation, a droplet delivery device. The method of claim 3,
Wherein the surface tension plate is located within 2 mm of the opening plate to create sufficient hydrostatic force to provide capillary flow between the surface tension plate and the opening plate. According to claim 1,
Wherein the opening plate comprises a dome shape. According to claim 1,
The opening plate is polyether ether ketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), Ni, NiCo, Pd, Pt, NiPd, metal alloys , And materials selected from the group consisting of combinations thereof. According to claim 1,
A droplet delivery device, wherein one or more of the plurality of apertures have different cross-sectional shapes or diameters to provide ejected droplets with different average ejection droplet diameters. According to claim 1,
A sufficient airflow located at the airflow inlet side of the housing and to facilitate layer airflow across the outlet side of the opening plate and to ensure that the discharged stream of droplets flows through the droplet delivery device during use. A droplet delivery device further comprising a laminar flow element configured to provide. The method of claim 8,
And a mouthpiece coupled to the housing opposite the laminar flow element. According to claim 1,
Wherein the ejector mechanism is oriented relative to the housing such that the ejected stream of droplets proceeds into and passes through the housing at approximately 90 degree orbit before exiting the housing. According to claim 1,
The reservoir is detachably coupled to the housing, a droplet delivery device. According to claim 1,
The reservoir is coupled to the ejector mechanism to form a combination reservoir/discharger mechanism module, and the combination reservoir/discharger mechanism module is detachably coupled to the housing. According to claim 1,
The droplet delivery device further comprises a wireless communication module. The method of claim 13,
The wireless communication module is a Bluetooth transmitter, a droplet delivery device. According to claim 1,
The device further comprises one or more sensors selected from infrared transmitters, photodetectors, additional pressure sensors, and combinations thereof. A breathing actuated droplet delivery device that delivers fluid as a discharged stream of droplets to a subject's disposal relationship,
housing;
A combination reservoir/discharger mechanism module that is in fluid communication with the housing to receive a volume of fluid and to generate a discharged stream of droplets;
The ejector mechanism comprising a piezoelectric actuator and an opening plate having a dome shape, wherein the opening plate has a plurality of openings formed through its thickness, and the piezoelectric actuator vibrates the opening plate by one frequency. The ejector mechanism operable to generate an ejected stream of droplets;
At least one differential pressure sensor located within the housing;
The at least one configured to activate the ejector mechanism to generate an ejected stream of droplets upon sensing a predetermined pressure change in the housing when an object exhales on the airflow outlet side of the housing Differential pressure sensor;
The ejector mechanism configured to generate an ejected stream of the droplets, wherein at least about 70% of the droplets have an average ejection droplet diameter of less than about 5 microns, such that at least about 70 of the mass of the ejected stream of droplets %, the droplet delivery device comprising the ejector mechanism, delivered to the subject's wasteful relationship in a breathable range during use. The method of claim 16,
The dome-shaped opening plate is polyether ether ketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), Ni, NiCo, Pd, Pt, NiPd, metal A droplet delivery device comprising a material selected from the group consisting of alloys, and combinations thereof. The method of claim 16,
A sufficient airflow located at the airflow inlet side of the housing and to facilitate layer airflow across the outlet side of the opening plate and to ensure that the discharged stream of droplets flows through the droplet delivery device during use. A droplet delivery device further comprising a laminar flow element configured to provide. The method of claim 16,
And a mouthpiece coupled to the housing opposite the laminar flow element. A method for filtering large droplets from aerosolized smoke using inertial forces,
Generating a discharged stream of droplets using the droplet delivery device of claim 1,
The ejector mechanism is oriented relative to the housing such that the ejected stream of droplets proceeds into and passes through the housing at approximately 90 degree trajectory change before exiting the housing; And
Droplets having a diameter greater than about 5 μm are deposited on the side walls of the housing due to inertial forces, without being transported through the droplet delivery device out into the entrained air stream to the object's disposal relationship. Method for filtering large droplets from aerosolized smoke using.

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